1. “5th anniversary Paediatric Regulation” PDCO Achievements
Daniel Brasseur PDCO European Medicines Agency

2. Paediatric Regulation2

3. Take home message
Good research in children is a need & time is needed to develop good research

4. Research Needs in Paediatric Medicines
Total Opinions (+&-)

5. Research Needs in Paediatric Medicines
PIP Opinions (= need) Total Opinions

6. Research Needs in Paediatric Medicines
PIP Opinions (= need) Total Opinions
70% out of 700

7. 7

8. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

9. Overview of PDCO Procedure
Adoption of Opinion, or
Request for Modification
Adoption of
Opinion
&
Final Report
Decision
Start
Clock
Stop
Clock
ReStart
Clock
60 DAYS
60 DAYS
Opportunity
for the
Company
to introduce
Modifications
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision 9 9

10. Overview PDCO of Procedure
Adoption of Opinion, or
Request for Modification
Adoption of
Opinion
&
Final Report
Decision
Start
Clock
Stop
Clock
ReStart
Clock
60 DAYS
60 DAYS
Opportunity
for the
Company
to introduce
Modifications
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision 10 10

11. Overview PDCO of Procedure
Adoption of Opinion, or
Request for Modification
Adoption of
Opinion
&
Final Report
Decision
Start
Clock
Stop
Clock
ReStart
Clock
60 DAYS
60 DAYS
Opportunity
for the
Company
to introduce
Modifications
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision 11 11

12. 12

13. 13

14. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

15. PDCO 5 CHMP members + 1 members per Member State not yet represented
6 members from families & HCP associations
Each member has an alternate 15 15

16. Rapporteurships

17. PIP Procedure First step = 7 “expert” inputs
Rapporteur’s
written
Contribution
Day 20
1st Rapp
Oral Present.
at PDCO
Day 30
1st PDCO Discussion
+OE?
Day 60
Start
Clock
Stop
Clock
Re-Start
Clock
EMA
Sm Report
Day 1
Peer Reviewer’s
Comments
Day 27
Members’
written
Comments
Day 30-55
Update EMA/
PDCO Report
Request for
Modification

18. PIP Procedure First step = 7 “expert” inputs
Rapporteur’s
written
Contribution
Day 20
1st Rapp
Oral Present.
at PDCO
Day 30
1st PDCO Discussion
+OE?
Day 60
Start
Clock
Stop
Clock
Re-Start
Clock
EMA
Sm Report
Day 1
Peer Reviewer’s
Comments
Day 27
Members’
written
Comments
Day 30-55
Update EMA/
PDCO Report
Request for
Modification

19. PIP Procedure Second step = 9 “expert” inputs
OE?
Final EMA Decision
Day 130
Company’s
PIP Re-
Submission
Day 61
EMA
Sm Report
Update
Day 71
2nd Rapp Oral
Present.
Day
& 2nd PDCO Discussion
+OE?
3rd PDCO
Discussion
Final Report
Day 120
Re-Start
Clock
PDCO
Opinion
EMEA
Decision
Rapporteur’s
Comments on Modifications
Day 80
PReviewer’s
Comments on Modifications
Day 88
Members’
Final Comments
to EMA
Day 105
Update
EMA/PDCO
Sm Report
Day 110
OE= oral explanation

20. 20

21. Evaluation procedure of PIPs
PDCO FWG Formulation Group – monthly meeting
PDCO members (Chair: Dr Siri Wang) + external experts (hospital, academia).
Discussion on formulation aspects and reporting to the PDCO.
PDCO Paediatric Committee - monthly meeting

22. Applications assessed by FWG
Around 1000 PIPs validated PIP/waiver applications (March 2011)
60%
15/m

23. Critical Points for Paediatric Formulations
Route of administration
Appropriate dosage forms
Excipients - 50% of the PIPs- choice excipient, safety, level, side effects……
Taste and palatability
Delivery devices
Rate of infusion
Volume to be administered
Wastage 23

24. Regulatory references 2
(Draft) Guideline on pharmaceutical development of medicines for paediatric use
Collaborative work between QWP, PDCO, and external experts.
Public consultation aimed very soon.

27. WGroups Non-Clinical Opportunity
Start
Clock
Stop
Clock
ReStart
Clock
Opinion
DAY 0 or 30
DAY 60 or 90
Opportunity
to discuss need for juvenile animal studies
Opportunity
to discuss need for juvenile animal studies

29. WGroups Methodology Opportunity Opportunity
Start
Clock
Stop
Clock
ReStart
Clock
Opinion
DAY 0 or 30
DAY 60 or 90
Opportunity
to discuss extrapolations statistics ?modelling
Opportunity
to discuss extrapolations statistics ?modelling

30. Reasonable to assume equivalence of disease Children = Adults
- similar progression?
- similar response to intervention? No
Yes
Yes
Conduct PK studies
Conduct S & E trials
Reasonable to assume similar concentration response (C-R) in Children = Adults? No
Yes
Is there a PD measurement that can be used to predict E?
Conduct PK studies to achieve levels similar to Adults
Conduct S trials No
Yes
Conduct PK/PD studies to get CR for PD measurement
Conduct PK to achieve target concentration based on CR
Conduct S & E trials

31. Prevalence Diagnosis Project Resources Protocol
Methodological constraints in small populations
Overall population
Prevalence
Affected population
Diagnosis
Sick population
(patients)
Project
Available Population
(volunteers)
Resources
Participating
Population
(Cases)
Protocol
“Classical Power” CT

32. Modelling and Simulation!

33. Definition of Models Published Paradigm
PBPK (Physiologically Based PK)
PBPK-PD
POP PK (Population Based PK)
POP PK/PD
Disease progression models and response models
Kinetic (K)–PD models
Toxicity/AE models

35. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

37. 60%

39. 6% How many trials have effectively started?
How many children to be included?
How many indications to be developed?
What is the expected product attrition rate?
What are finalisation delays overall? 6%

40. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

41. REPORT ON THE SURVEY OF ALL PAEDIATRIC USES OF MEDICINAL PRODUCTS IN EUROPE
established according to article 42
of Regulation (EC) No 1901/2006
of the European Parliament and of the Council
on medicinal products for paediatric use
Presented by: Dr. Radu Botgros
Scientific Administrator, Safety and Efficacy of Medicines

42. Results (I) mainly in Scandinavia.
Most frequent medicines used off-label/ unauthorised:
antiarrhythmics,
antihypertensives (rennin-angiotensin inhibitors and beta- blockers),
proton pump inhibitors and H2-receptor antagonists,
antiasthmatics, and
antidepressants (mainly selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants).
High rate of off-label use of oral contraceptives in ados
mainly in Scandinavia.

43. Results (II) Extensive off-label use of ABs in very young children.
macrolides
betalactamines plus betalactamase inhibitors
carbapenems
Corticosteroids used off-label in the systemic treatment of very young children.
Some for systemic use (e.g. dexamethasone) are not even authorised in some countries (Norway)

44. Results (III) Analysis of the pharmaceutical forms off-label use of
both oral and parenteral formulations are being used unauthorised or off-label,
common reason: lack of appropriate dosages and strengths for the treated age groups.
off-label use of
multivitamins
many antiasthmatics.

45. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

46. 46

47. DG Research evaluation
List
DG Research evaluation
Applicant’s project
Funding
DG Research
EMA
PDCO evaluation
PIP 47

48. DG Research evaluation
List
DG Research evaluation
Applicant’s project
Funding
DG Research
EMA
PDCO evaluation
PIP 48

49. List
Applicant’s draft PIP
PDCO
DG Research
EMA
PIP 49

50. Applicant’s project + agreed PIP
List
PDCO
Funding
DG Research
EMEA
PIP
Applicant’s project + agreed PIP 50

51. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

52. Academia
Researcher
Regulators
HCP
Industry

53. PDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges

57. Scientific Advice (paediatric only)
SA +PA
Paed %
2007
281
7.5
2008
320
7.2
2009
388
7.7
2010
400 8 57 57

58. PDCO Achievements Conclusion
Change of mindset with Industry
475 PIPs agreed
Start of Network of Networks
Limited view of immediate impact…
Better overview of Paediatric needs
Trials of off-label drugs (FP7)
Reflection ongoing to improve/ facilitate work

59. Take home message
Good research in children is a need & time is needed to develop good research