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  ADEDIEM / Master of International Drug
  Development and Registration 3rd FEB 2006

The Planned EU Pediatric Regulation
– An Industry Perspective -

   Klaus Rose, Head Pediatrics, Medical Science PDM5,
   F. Hoffmann-La Roche Pharmaceuticals, Basel, Switzerland

Klaus Rose Chatenay-Malabry 03FEB2006   -1-

•    Drug development: global vs. regional perspective
•    Facilitation of pediatric research by US legislation
•    Planned EU pediatric regulation: challenges & opportunities
•    Near & middle future consequences
•    The objective of the EU commission and the EMEA – A reality
•    Outlook

Klaus Rose Chatenay-Malabry 03FEB2006   -2-
Drug Development & National States

 •    Comparing 2006 with 1956 and 1906, we see a shrinking
      number of world players in pharmaceutical industry
 •    Their research & development is planned & done globally
 •    Discovery companies come and go. Successful discoveries are
      licensed in & channeled thru global pharmaceutical companies
 •    Submission, coordinated globally within each company, is to
      local Health Authorities - who accept global ICH
 •    A regional government needs to consider this background for
      any regulation, including pediatric drug development

Klaus Rose Chatenay-Malabry 03FEB2006   -3-
Pediatric Drug Development: Perspectives (1)

Clinical Perspective                    Product Perspective
• Reduce off-label use of               • Pediatric development
    existing drugs                         causes additional costs
                                        • Research for old drugs
• Encourage research in
                                           needs public funding – [or could
    pediatric diseases
                                           increased generics‘ price help
• Ensure that children benefit             finance pediatric research?]
    early from new drugs
                                        • Patent protected drugs: finance
• Let pediatricians participate            research through incentives
    more in global drug develop-
                                        • Drugs of the future: Mandatory
                                           pediatric development and

Klaus Rose Chatenay-Malabry 03FEB2006   -4-
Pediatric Drug Development: Perspectives (2)

  Clinical Perspective                            Product Perspective
• Clinicians provide consulting                   •   Pediatric development
   to both HAs and companies                          plans are negotiated
•      Pediatricians execute the trials               between companies
       agreed upon between                            and HAs
       companies and Health                       •   The terms of performing
       Authorities (HAs)                              individual clinical trials are
                                                      negotiated with clinicians
                                                  •   Companies provide the
                                                      trials‘ organisational
                                                      backbone, reporting, and
                                                      filing of results

    Klaus Rose Chatenay-Malabry 03FEB2006   -5-

 •    EU-triggered increased demand of pediatric research will
      not automatically mean more pediatric research in Europe
 •    Pediatric legislations do not fundamentally change the
      scope of drug development. They lead to inclusion of
      pediatric thinking into a drug development that at present
      aims at large adult markets
 •    Increasing understanding of molecular and genetic bases of
      diseases will lead to more tailor-made disease targets
 •    Rare diseases, including child diseases, will be a natural
      part of these personalized disease targets
 •    Scepticism against clinical research in children is still strong
 •    Pediatric legislations have already helped considerabley to
      remove mental barriers against pediatric drug research
Klaus Rose Chatenay-Malabry 03FEB2006   -6-
Pediatric Research:

US Legislation established Framework
•    Volontary Pediatric Exclusivity: FDAMA* 1997, BPCA** 2002
•    Mandatory pediatric development: PREA*** 2003
•    Both legislations are linked and sunset 30 September 2007
•    Global companies put pediatric assessments today into their
     standard development plans to comply with FDA
•    EU pediatric regulation debate does not start de novo
•    Ten years of US experience, learning, and research are part
     of the fundament of the current debate and need reflection
*FDAMA FDA Modernization Act **BPCA Best Pharmaceuticals for Children Act
***PREA Pediatric Research Equity Act
Klaus Rose Chatenay-Malabry 03FEB2006   -7-
What Research Is Stimulated By BPCA?

 • Intention: reduce off-label use and stimulate pediatric research
 • Potential research targets: any medically relevant off-label use
 • Deliverable: research performed. Not a positive result
 • Most patent protected drugs have now US PE data on:
  – PK/PD and dosing in younger populations
  – Pediatric formulations
  – Counterindications in children
  – New indications
 • Granted WRs and PEs cover a wide range
  – Same indications as in adults investigated in children
  – Completely different indications investigated in children

 Klaus Rose Chatenay-Malabry 03FEB2006   -8-
Pediatric Exclusivities: Examples

•   Orlistat (Xenical): Obesity of adolescents
•   Oseltamivir (Tamiflu): Influenza in children 1-12 years old
•   Atorvastatin (Lipitor): new indication heterozygous familial
•   Tamoxifen: safety & efficacy in McCune-Albright Syndrom
•   Alendronate: safety & efficacy in osteogenesis imperfecta (OI)
•   Vinolrebine: Negative result (“no meaningful clinical activity“) of
    investigation of safety & efficacy in tumors including rhabdo-
    myosarcoma / undifferentiated sarcoma, neuroblastoma, & CNS.

Klaus Rose Chatenay-Malabry 03FEB2006   -9-
Which Research Might Be EU-Triggered?(1)

• The most obvious and immediate targets for modern, patent-
  protected drugs were covered by the US-triggered research
• E.g. antihypertensives: Hypertension in children
• Most patent-protected modern drugs are also used in Europe
• A lot of clinically meaningful research targets remain for these
  drugs: new indications, new age groups, longer observation time ….
  and: rare diseases
  -   While EU debate goes on, patent time is running out
  -   Will need creativity and dedication in industry, HAs and clinicians
  -   Will be an interpretation of the regulation
  -   Will not happen without lobbying from industry and pediatricians

 Klaus Rose Chatenay-Malabry 03FEB2006   - 10 -
Which Research Might BE EU-Triggered?(2)

• EU-initiated additional research projects in
  - New indications
  - Additional age groups
  - Studies with longer observation time
  - Rare diseases where patent-protected drugs have a therapeutic
  … would constitute a second wave of pediatric research after the
   first wave triggered by the US legislation
EU doesn‘t start from zero. A lot was done since 1997
Now is the time to start reflecting about concrete projects
Parents & patients need to be involved into this debate

 Klaus Rose Chatenay-Malabry 03FEB2006   - 11 -
Future Drugs, Registration 2007 & Later

•   It will take time until the Pediatric Committee (PC) is functional
•   All drugs that will be submitted to the PC in 2007 to 2010 will
    already have had a pediatric plan submitted to FDA
•   With few exceptions, clinical pediatric development in new drugs
    will start after adult registration ( deferral @ registration)
•   Global companies will then have already clear ideas about
    pediatric development after the deferral

Klaus Rose Chatenay-Malabry 03FEB2006   - 12 -
      Theses 1

  •    The draft ped regulation expresses the will of the EU
       commission to stimulate pediatric research in Europe
  •    A reality check of other Commission plans shows that they
       do not become reality automatically
  •    The 2000 Lisbon agenda planned for Europe to be the most
       competitive economic zone, based on knowledge & science.
       Since then, EU‘s competitiveness has continuously declined
  •    Where will we go with the pediatric regulation?

Klaus Rose Chatenay-Malabry 03FEB2006   - 13 -
Theses 2

Mandatory Part of EU Ped Regulation
•   For new drug MAAs, FDA-approved pediatric development
    plans will exist and will be submitted to the PC. Companies
    will ask to limit pediatric research to these plans.
•   For submission of new indications, formulations & routes of
    administration for marketed drugs, PIP will be a condition &
    additional burden. Economic logic will make companies ask for
    very limited research. Clinical logic will make the PC ask for
    extended research. Might result in
    - reluctance to submit new indications, formulations etc., and/or
    - delay of new indications, formulations for adults
•   Strong emphasis on penalties (“…shall be effective, proportionate
    and dissuasive“ §48). Pressure does not encourage creativity

Klaus Rose Chatenay-Malabry 03FEB2006   - 14 -
Theses 3    Rewarded Pediatric Research

 •    With the exception of biologics & some antibiotics, most modern
      drugs have a PE program ongoing or already finalized
 •    These research programs will not receive 2nd EU reward
 •    Only those drugs with a prolongable SPC beyond expiry of data
      protection are eligible for an additional EU reward
 •    Additional reward for additional research is not addressed
      directly in the regulation and will require its interpretation
 •    As the PC will be constituted within 6 months after entry into
      force of the regulation, no binding comittment is possible now
 •    With time the number of drugs with prolangable SPC i.e. of
      potential research projects is declining

Klaus Rose Chatenay-Malabry 03FEB2006   - 15 -
Theses 4

•      In the long term, global companies will have FDA and EMEA
       as dialogue partners to design pediatric development plans
•      At present companies talk more with FDA about drugs of the
       future and their pediatric development
•      For drugs registered 2010 and later it is at present undefined
       which additional requests the EMEA PC will make
•      A global agreement would be desirable on one global
       pediatric development plan, valid in all regions, covering both
       data acceptance by Health Authorities and rewards in the
       different regions. This will certainly take much more time

    Klaus Rose Chatenay-Malabry 03FEB2006   - 16 -
Consequences of Pediatric Legislations

• Common feature PREA / EU: Pediatric Assessment (PA) and
  Pediatric Investigation Plan (PIP): companies will have to think
  of children early – together with Health Authorities!
• Companies will have to increase their pediatric competency
  - Build up pediatric department, or ...
  - Establish cross-functional expert group with sufficient senior
    management support, or ...
  - Buy external competence @ appropriate consultant or ...
  - EU or Japan based companies should use time to prepare
• Health Authorities will increase competency & demands
• New technologies will be increasingly used, e.g. PK/PD
  modelling, trial simulation, extrapolation for appropriate dosing in
  younger age groups, new statistical approaches
 Klaus Rose Chatenay-Malabry 03FEB2006   - 17 -

•    The objective of the EU Commission to facilitate pediatric
     research in Europe is laudable
•    It adds momentum to the movement initiated by the USA and
     helps to remove mental barriers
•    The concrete outcome of the regulation is yet undecided
•    Each company will have to make good proposals to EMEA
•    Pediatricians need to develop their European voice
•    For pharmaceutical industry this is a challenge to prove the
     committment to child health care
•    The dialogue between the partners in child health care –
     pediatric clinicians, regulators, pharmaceutical industry,
     patient organisations and others must be intensified.

Klaus Rose Chatenay-Malabry 03FEB2006   - 18 -
          Thank You!

Klaus Rose Chatenay-Malabry 03FEB2006   - 19 -

Klaus Rose Chatenay-Malabry 03FEB2006   - 20 -
  EU Pediatric Regulation
  Objective and Timelines
     To introduce scientific and regulatory measures to encourage
      the research, development and authorisation of medicinal
      products for the use in the paediatric population.
     To provide incentives to support pediatric investigations into new
      and older products.
     To create and support a pediatric R&D structure.

                                            Modified Commission
                         Draft Commission         proposal      Legislative
                              proposal                           Process
–European Health                                                               into force:
 Council Resolution                   1st Reading          2nd Reading
–Consultation paper of
 the Commission                                                          ...
 2004                           2005
Klaus Rose Chatenay-Malabry 03FEB2006           - 21 -
 EU Paediatric Regulation
 Key Elements
           REQUIREMENTS                            INCENTIVES

• Agreement of a Paediatric                  • Rewards/Incentives = 6-
  Investigation Plan (PIP)                     month SPC extension for
     → Timing/measures for all subsets         drugs with patent/ SPC
       of the paediatric population            protection
• Requirement to submit                      • Special paediatric MA
  paediatric data with the MAA                 (PUMA) for drugs without
  unless waiver or deferral is                 patent/ SPC protection
                                             • For orphan medicinal
• Requirement to submit                        products 12 years market
  paediatric data/ waiver/ deferral            exclusivity
  for line extensions
Klaus Rose Chatenay-Malabry 03FEB2006    - 22 -
 EU Pediatric Regulation
 Requirements to qualify for incentives for on-patent products:
    – Pediatric data to be generated in compliance with an agreed PIP.
    – Pediatric information needs to go in the SmPC.
    – Approval in all Member States.
    – No other incentive apart from an SPC extension is being granted.
    – Exclusion of data submitted outside the EU at time of coming into force of
      the Regulation.
    – Application for SPC extension based on amended SmPC and to be
      logged 2 years prior to the SPC extension date.

        Key differences compared to the US Legislation (BPCA):
        Extension granted based SmPC change and not just
         data availability (potential timing issue)
        Applicable to both Drugs and Biologics
Klaus Rose Chatenay-Malabry 03FEB2006    - 23 -
When Should Drug Development Start

In Children? - ICH E 11 Scenarios -
1. Medicinal products for diseases predominantly or
   exclusively affecting children
   Development in children only, e.g. lung surfactant
2. Medicinal products intended to treat serious or life-
   threatening diseases, occurring in both adults and children,
   and currently no or limited therapeutic options available
   Pediatric development should begin early after initial safety
     data and reasonable evidence of benefit
3. Medicinal products for other diseases and conditions
   Less urgent in children, start development in phase IIIb/IV

Klaus Rose Chatenay-Malabry 03FEB2006   - 24 -
Consequences of Early Start of
Pediatric Envolvement
   • To the child: risk of exposure to a new substance
   • The company: allocation of additional resources
   • Shifts many development steps into an earlier stage
   • All these investments are lost if the project is abandoned

   → Needs to be carefully considered case by case based on
      – Mechanism of disease in children
      – Risk / benefit assessment
      – Frequency of the disease in children
      – If applicable, specifically for the different age groups

Klaus Rose Chatenay-Malabry 03FEB2006   - 25 -
   Accelerated Pediatric Development:

        Preclinical            Ph I                            Ph IIa                                            Ph IIb                              Ph III                      Ph IV

                                   Pre-IND                            (EoPh2a                                             EoPh2b                                  Pre-subm.     Sub. Dossier
                                   Mtg.                                 Mtg)                                              Mtg.                                    Mtg.          ped & adults
                  pediatric                     PoC/PoE
                                                                                                                                                 Pivotal & LT safety adults
                  assessment                     adults

               Decide about                                                           PK ped
               requested waivers
               / deferrals                                                           Taste trial(s)

                                                                                Bioequivalence    DF pediatric
                                                                                   Studies                                                      Pivotal & LT safety pediatric

                                                                                                                      Dosage strengths

                                                                        Paediatric Formulation(s) from Early Phase over Pilot to Final Market Formulation

    Analytical method development                Route feasibility feed
Blood dist./proteinbg. across species               mouse, rat (car)                 Carcinogenicity p.o. mouse, rat
 in vitro metabolism across species            13w DRF mouse, rat (car)                Local tolerability i.v. rabbit
        Radiolabeled synthesis                Safety pharmacology suppl.                  Mechanistic toxicity
        Rat ADME, QWBAR i.v.                  26w tox study p.o., rat, dog               2w i.v. toxicity rat, dog
       p.o. rising dose/rat & dog            Embryofetal dev po DRF rabbit             Ames & V79CA impurities
         Safety pharmacology                 Embryofetal Dev po rabbit, rat            39w tox p.o. dog, monkey
         Ames test (5 strains)
                                             Fert. early. embr. dev, po, rat
in vitro mutation in mammalian cells
                                               Pre-/Post natal p.o., rat
p.o. 2-4w tox study in rats (incl.TK)
                                                  Milk excretion study
p.o. 2-4w tox study in dogs (incl. K)
  i.v. acute tox study in rats & mice

    Klaus Rose Chatenay-Malabry 03FEB2006                                                        - 26 -
Pediatric Drug Development (2)
• Introduction of pediatric thinking has a profound impact on the
  drug development process even if no decision is made to
  develop early in children
• Requires pediatric assessments at various decision points
• Requires generation of additional age specific data, e.g.
  - epidemiology,
  - mechanism of disease,
  - ADME* in children
• Requires re-tuning of the development process & machinerie
  - Training programs, monitoring of pediatric projects, regular
    reports to decision boards
*ADME: Absorption, Distribution, Metabolisation, Excretion
Klaus Rose Chatenay-Malabry 03FEB2006   - 27 -
 Specific Pediatric Assessments
• Epidemiology of targeted disease in children both in
  developed and developing countries
• Expected efficacy in children
• Age dependence of course & outcome of targeted disease
• Metabolism, bioavailability, distribution over age groups
• Availability of pharmacodynamic endpoints
• Extrinsic and intrinsic factors influencing PK in children
• Pharmacodynamic endpoints for PK/PD bridging
• Optimal timing of toxicology studies
• Additional cost/sales estimate in the pediatric population

 Klaus Rose Chatenay-Malabry 03FEB2006   - 28 -

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