EU Paediatric Regulation: Strategic Challenges and Opportunities for the Pharmaceutical Industry

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EU Paediatric Regulation Strategic Challenges
and Opportunities for the Pharmaceutical Industry

IFAPP 19 October 2007
Klaus Rose, Head Pediatrics, Roche Pharma
Development klaus.rose_at_roche.com
Disclaimer This presentation reflects Klaus
Roses personal opinion and is not an official
position of Roche Pharmaceuticals
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New Paradigm Of Drug Development

• Shift from protecting children against clinical
  research to protect children through clinical
  research
• Governments drive it by incentives mandatory
  requirements
• Links the profitable adult market to the
  pediatric population
• ? Challenges opportunities. We cannot ignore

Old Paradigm
Pediatric Development
Adult Development
New Paradigm
Adult and Pediatric Development
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Inclusion Of Children Into Drug Development
Process Started With Two US Legislations

• Voluntary Pediatric Exclusivity (PE) FDAMA 1997
  BPCA 2002. Biologics excluded.
• Mandatory ped development PREA 2003. All age
  groups. Biologics included. Applies to same
  indication as in adults only.
• Both are linked and were re-authorized autumn
  2007

• FDAMA / BPCA resulted in multiple pediatric
  research on patented drugs. Seen by FDA as major
  success
• Experiences with PREA are evolving

FDAMA FDA Modernization Act BPCA Best
Pharmaceuticals for Children Act PREA
Pediatric Research Equity Act
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EU Pediatric Regulation

• In force since January 2007
• Combines mandatory development with
  reward
• Pediatric Investigation Plan (PIP) mandatory end
  of Phase 1
• PIP must cover all age groups
• Pediatric Committee (PDCO) 27 assigned by EU
  member states 6 patient health professional
  representatives
• PDCO will assess PIPs decide on waivers
  deferrals
• Reward of six months SPC prolongation
• Transition phase until July 2008 (new drugs) /
  January 2009 (old drugs new indications /
  formulations / route of administration)

SPC Supplementary Protection Certificate
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Flexible Timing Of Discussion With FDA
Corresponding To Severity Of Disease
Phase I Phase II
Phase III Phase IV
EoPh I
NDA
Pre-IND
EoPII
Life threatening disease pediatric plan
(PP) strongly encouraged
Life threatening disease early dialogue
advised
Serious, not life threatening, alternatives
available PP discussion strongly
encouraged. ? deferral
Disease non existing in children waiver _at_
NDA approval
Always project-specific consideration
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EU Pediatric Regulation Requirements Independent
Of Disease Severity
Phase I Phase II Phase III
Phase IV
PIP
Amendments
Amendments
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Teams Clinical Homework Pediatrics

• Is targeted indication life-threatening or
  seriously disabiliting?
• Does the same or another indication exist in
  children? - Including frequency per age group
  mechanism of disease
• Therapeutic alternatives in children?
• Research literature public data bases, get KOL
  insights
• Risk/benefit assessment on start of clinical
  trials in children

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Ped Drug Development Clinical Algorithm
Consider early pediatric development
Are there alternative treatments available?
Is there a pediatric condition potentially
treated with your drug?
Is the pediatric condition severe or life
threatening?
No
Yes
Yes
Yes
No
No
Prepare waiver PIP/PREA
Considerddeferral PIP/PREA
Consider deferral PIP/PREA
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Integrating Pediatric Aspects Into The General
Drug Development Process

• Three major challenges
• Off-label pediatric use of existing medications
  fine-tuning
• Development projects now in clinical phase 2/3
• Include children in de novo development
• Is cross-functional challenge that involves all
  major functions clinical, regulatory,
  technical, pre-clinical development, clinical
  pharmacology, modelling simulation, statistics,
  marketing, government liaison, media liaison, and
  many more
• Increased pressure for innovation generates
  additional costs ? One more factor that increases
  the survival pressure
• ? Business opportunity of 6 months added
  exclusivity
• As it is a given, deal with it as smart as
  possible

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Special Case Oncology

• Industry aims at adult cancer which develops
  through decades of cell exposure to pleasure /
  noxious environment smoking, alcohol, modern
  food, etc
• We treat e.g. colorectal, breast, pancreas, lung
  cancer - solid cancers that do not exist in
  children
• and
• ? Clinicians RAs expect use of modern drugs in
  child cancer
• Reward is offered for treatment of other
  pediatric cancer types
• Most challenging therapeutic area with largest
  gap between adult and child medicine

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Cancer in Children 1

• Rare in comparison to adult cancer, but most
  common fatal disease in children gt1 year in USA /
  EU
• Biology distribution different from adult
  cancer
• Different cancer types relatively frequent at
  different age groups
• Cure rate 80 by combining chemo, radiation,
  surgery
• Most drugs used today were developed in the
  1950ies / 60ies
• Almost all patients treated in trials by
  collaborative groups who are extremely well
  organized and politically connected
• They systematically scan modern drugs for
  potential use
• Place of modern targeted medicines yet to be
  shaped
• We are suddenly in the eye of this hurricane

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Age specific - Osteosarcoma
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Age specific - Neuroblastoma
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Survival after Childhood Cancer
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Cancer in Children 2

• Cancer seen today as malfunctioning signal
  transduction in the tumor cell / between tumor
  cells and other cells / environment
• Targeted therapy aims at modifying this signal
  transduction
• Hope of pediatric oncologists to also use
  therapeutic potential of targeted therapies
• AND
• ? Rarity of child cancer prohibits large
  randomized DBPC trials
• ? Adult cancer drugs aim upfront at different
  targets
• ? Role of preclinical testing gaining weight

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Oncology Early Pipeline Exploratory Thoughts

• Until now industry let academia / collaborative
  groups have the lead in pediatric oncology.
  Industry supported by medication and grants
• Politics are going to change this
• Part of collaborative groups work will shift
  towards industry
• FDA / EMEA requirements now different but
  converging
• Possible next scenario look into tumor type, not
  indication

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Other Therapeutic Areas

• General tendency to go nearer to the biology of
  the diseases target receptors/ signal
  transduction etc.
• In the mean long term ? companies will need
  more competence on expression of these receptors/
  signal transduction ways etc. in children
• Is pediatric asthma/ rheumatoid arthritis/
  obesity the same disease as in adults?
• What is the mechanism of associated illnesses,
  e.g. secondary hypertension in obese children?
• How will EMEA / PDCO deal with medication
  classes, e.g. chimeric vs. humanized vs. human
  MABs with the same target?

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Challenges Opportunities For Industry

• Legislations dont change the general scope of
  drug development
• They link adult market to children ? pediatric
  use of our drugs
• EU regulation doesnt exclude biologics ? High EU
  impact
• All EU parties are on learning curve - with
  progress the number of open questions is
  increasing
• Shift of political exposure from countries to
  pan-EU scenario
• Most imminent challenges of oncology other areas
  coming
• Pressure for innovation on industry, clin
  academia regulators
• Continuing dialogue between the partners in
  healthcare is crucial

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• Thank You!

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• Back-Ups

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• FDA-Stimulated Voluntary
• Pediatric Research

• Potential research targets clinically 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 written requests (WRs) and pediatric
  exclusivities (PEs) cover a wide range
• Same indications as in adults investigated in
  children
• Completely different indications investigated in
  children

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• Granted US WRs Examples

• Xenical Obesity of adolescents (PE)
• Tamiflu Influenza in children 1-12 years (PE)
• Lipitor heterozygous familial hypercholesterolemi
  a (PE)
• Tamoxifen McCune-Albright Syndrom PE)
• Alendronate osteogenesis imperfecta (PE)
• Viagra neonatal pulmonary hypertension (WR)
• Detailed statistics www.fda.gov

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• Which Research Is Stimulated By PREA?

• PREA is mandatory
• Restricted to same indication in children as in
  adults
• Covers chemical products as well as biologics
• Orphan drugs are exempted from PREA
• FDA has for several medicines invoked PREA when
  companies refused initially issued WRs
• Understanding of how PREA is enforced is
  evolving.
• Consideration of pediatrics in the drug
  development process started for US-based and
  global companies with mandatory FDA requirements

PREA Pediatric Research Equity Act , mandatory

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It is currently estimated that 1 out of 650
healthy people is a cured or long survivor
from cancer in younger age. (Meadows,2003)
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Roche Pediatric Group General Structure
Medical Science
Clinical Operations
RPG
Business
Research
Communication
Regulatory
Technical
Extended Audience
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ICH Guidance Pediatric Age Groups
Term newborn infants(0 - 27 days)
Infants and toddlers(2 to 23 months)
Children(2 - 11 years)
Adolescents(12 to 16-18 years) US 16 years/ EU
18 years
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Special Requirements in Pediatric Clinical Trials

• Informed Consent
• Assent from children 6-13 years and adolescents
• Consent from the legal representative
• Limited use of placebo
• Only if no approved therapies
• DSB for serious disease or escape criteria for
  less serious conditions
• Specific efficacy and safety measurements
• Children not able to perform (spirometry)
• Minimal invasiveness of examinations (number
  volume of samples)
• Child and family friendly research facilities

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Pediatric Non-clinical Algorithm
Is there a concern (based on pharmacology or
findings relevant for developing organ systems)
that can not be adequately and safely tested in
pediatric clinical trials
Initiate juvenile animal study with timing of
dosing in relation to phases of growth and
development of organs at risk in pediatric
population
Propose study design for juvenile animals
accepted by authorities
Existing adult animal human safety data
sufficient?
yes
no
yes
Conduct non-clinical metabolism studies to assist
in the selection of model for juvenile animal
studies
yes
no
Measure exposure
Generally no need for non-clinical safety
studies in juvenile animals
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Pediatric Formulation Algorithm
Extemporenous formulation for clinical trials
Final formulation to be ready for Phase III trials
Is the drug in capsule or tablets
What age group will be treated with the drug?
Yes
lt 8 yrs
Preliminary liquid formulation for clinical trials
gt 8 yrs
No
Use adult formulation for pediatric development
Parenteral or Liquid formulation excepients safe
for children?
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Pediatric Dose Prediction Algorithm
Body weight
Final pediatric dose recommendation to be ready
for Phase III trials
What age group will be treated with the drug
Calculation of pediatric dose for clinical trials
lt 15 yrs
Or Body surface area
?
Is there adult PK population model available
?
?
gt 15 yrs
Or Physiology model
Pediatric population PK study during Phase II
Phase 1 Classical PK/PD study
Use adult dose for pediatric development
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Conference on Pediatric Oncology 15th November
2007 in London, UK

• Jointly organized between EMEA, DIA, EFGCP
• Steering committee
• Ralf Herzog, EMEA
• Gilles Vassal, ITCC
• Bruce Moreland, UK childrens oncology group
  ITCC
• Klaus Rose, Roche
• Additional faculty members
• Kathy Pritchard-Jones, SIOP Europe
• Karen Weiss, FDA
• Hans Stoetter, SwissMedic