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An agency of the European Union
Daniel Brasseur PDCO European Medicines Agency
““55thth anniversary Paediatric Regulation” anniversary Paediatric Regulation”
PDCO AchievementsPDCO Achievements
2
2
Paediatric Regulation
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 (+&-) 700
5
Research Needs in Paediatric Medicines
PIP Opinions (= need) 500
Total Opinions 700
6
Research Needs in Paediatric Medicines
PIP Opinions (= need) 500
Total Opinions 700
70% out of 700
77
8
PDCO AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
99
9
Overview of PDCO Procedure
ReStartClock
StopClock60 DAYS60 DAYS 60 DAYS60 DAYS
Adoption of
Opinion&
Final Report
StartClock
DecisionDecision
Evaluate ChangesFind AgreementFinalize PlanPublish Decision
Opportunity for the
Company to introduce Modifications
Understand PlanDetect ProblemsIdentify ExpertsPropose Changes
Adoption of Opinion,
orRequest for Modification
1010
10
Overview PDCO of Procedure
ReStartClock
StopClock60 DAYS60 DAYS 60 DAYS60 DAYS
Adoption of
Opinion&
Final Report
StartClock
DecisionDecision
Evaluate ChangesFind AgreementFinalize PlanPublish Decision
Opportunity for the
Company to introduce Modifications
Understand PlanDetect ProblemsIdentify ExpertsPropose Changes
Adoption of Opinion,
orRequest for Modification
1111
11
Overview PDCO of Procedure
ReStartClock
StopClock60 DAYS60 DAYS 60 DAYS60 DAYS
Adoption of
Opinion&
Final Report
StartClock
DecisionDecision
Evaluate ChangesFind AgreementFinalize PlanPublish Decision
Opportunity for the
Company to introduce Modifications
Understand PlanDetect ProblemsIdentify ExpertsPropose Changes
Adoption of Opinion,
orRequest for Modification
1212
1313
14
PDCO AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
1515
15
5 CHMP members+
1 members per Member State not yet represented
+6 members from families
& HCP associations
Each member has an alternate
PDCO PDCO
16
Rapporteurships
0
10
20
30
40
50
60
70
Aus
tria
Be
lgiu
m
Bulg
aria
Czec
h Re
publ
ic
D
enm
ark
Esto
nia
Fi
nlan
d
Fr
ance
G
erm
any
Hea
lthca
re a
nd A
cade
mia
Hun
gary
Ic
elan
Irel
and
Ita
ly
La
tvia
Lith
uani
a
Luxe
mbo
urg
M
alta
N
orw
ay
Pa
tient
s' O
rgan
isati
on
Pola
nd
Port
ugal
Ro
man
ia
Slov
enia
Spai
n
Swed
en
The
Net
herl
ands
U
nite
d Ki
ngdo
m
17
Update EMA/PDCO ReportRequest forModification
PIP Procedure First step = 7 “expert” inputs
Re-StartRe-StartClockClock
StopStopClockClock
Peer Reviewer’sComments
Day 27
Rapporteur’swritten
ContributionDay 20
Members’written
CommentsDay 30-55
StartStartClockClock
1st Rapp Oral Present.
at PDCODay 30
1st PDCO Discussion
+OE?Day 60
EMASm Report
Day 1
18
Update EMA/PDCO ReportRequest forModification
PIP Procedure First step = 7 “expert” inputs
Re-StartRe-StartClockClock
StopStopClockClock
Peer Reviewer’sComments
Day 27
Rapporteur’swritten
ContributionDay 20
Members’written
CommentsDay 30-55
StartStartClockClock
1st Rapp Oral Present.
at PDCODay 30
1st PDCO Discussion
+OE?Day 60
EMASm Report
Day 1
19
PIP Procedure Second step = 9 “expert” inputs
3rd PDCODiscussion
Final ReportDay 120
OE= oral explanation
Rapporteur’s Comments on Modifications
Day 80
PReviewer’s Comments on Modifications
Day 88
UpdateEMA/PDCOSm ReportDay 110
Members’Final Comments
to EMADay 105
PDCOPDCOOpinionOpinion
EMEAEMEADecisionDecision
Re-StartRe-StartClockClock
Company’sPIP Re-
SubmissionDay 61
EMASm Report
UpdateDay 71
2nd Rapp Oral
Present.
Day
& 2nd PDCO Discussion
+OE?90 .
OE?Final EMA DecisionDay 130
20
20
21
Evaluation procedure of PIPsEvaluation 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 FWGApplications assessed by FWG
Around 1000 PIPs
validated PIP/waiver
applications
(March 2011)
5484
220
0
50
100
150
200
250
2008 2009 2010-2011
PIPs reviewed by Quality Sector
No. of PIPs60%
15/m
2323
Critical Points for Paediatric FormulationsCritical 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
24
Regulatory references 2 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.
25
26
27
WGroups
ReStartClock
StopClockDAY 0 or 30DAY 0 or 30 DAY 60 or 90DAY 60 or 90
StartClock
Opinion
Opportunity to discuss need for
juvenile animalstudies
Opportunity to discuss need for
juvenile animalstudies
Non-Clinical
28
NcWG discussions November 2008 - September 2011
0
5
10
15
20
25
Num
ber
of P
IPs
disc
usse
d
Re-discussions
New PIPs
29
WGroups
ReStartClock
StopClockDAY 0 or 30DAY 0 or 30 DAY 60 or 90DAY 60 or 90
StartClock
Opinion
Opportunity to discuss
extrapolations statistics
?modelling
MethodologyMethodology
Opportunity to discuss
extrapolations statistics
?modelling
30
Reasonable to assume equivalence of disease Children = Adults- similar progression?- similar response to intervention?
Reasonable to assume similar concentration response (C-R)
in Children = Adults?
Conduct PKPK studiesConduct S S & EE trials
Conduct PK studies to achieve levels similar to Adults Conduct SS trials
Conduct PKPK/PDPD studies to get CR for PD measurementConduct PKPK to achieve target concentration based on CRConduct SS & EE trials
Is there a PD measurement
that can be used to predict EE?
NoNo
NoNo
NoNo
YesYes
YesYes
YesYes
YesYes
31 “Classical Power”
Overall population
Affected population
Sick population (patients)
Available Population(volunteers) Resources
Project
Diagnosis
Prevalence
Participating Population (Cases)
Protocol
CT
Methodological constraints in small populations
32
Modelling and Simulation!
33
Definition of ModelsPublished 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
34
35
PDCO AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
36
37
60%
38
39
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 AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
An agency of the European Union
Presented by: Dr. Radu BotgrosScientific Administrator, Safety and Efficacy of Medicines
REPORT ON THE SURVEY OF ALL PAEDIATRIC USES OF MEDICINAL PRODUCTS IN EUROPEestablished according to article 42of Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use
42
Results (I)
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
• 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 AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
4646
4747
PDCOevaluation
List DG Research
evaluation
PIP
DG Research
EMA
Funding
Applicant’sproject
4848
PDCOevaluation
List DG Research
evaluation
PIP
DG Research
EMA
Funding
Applicant’sproject
4949
PDCO
PIP
List
DG Research EMA
Applicant’sdraft PIP
5050
PDCO
PIP
List
DG Research EMEA
Applicant’s project + agreed PIP
Funding
51
PDCO AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
52
Researcher
HCP
Industry
Regulators
Academia
53
PDCO AchievementsPDCO Achievements Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
54EFPIA/EMA Infoday - 23 May 2011 1
Efpia survey on impact of the paediatric regulation on marketing authorization holders (Jan 2007 – Jun 2010)
Judith Creba (Novartis Pharma)
Craig Johnson (Eli Lilly)
Angelika Joos (Merck Sharp & Dome)
23 May 2011
55EFPIA/EMA Infoday - 23 May 2011 6
34 companies provided input
biologicals
56
Timing of Art.7 PIP submissions for new medicinal products (information received on N=146 out of 168 submitted PIPs)
EFPIA/EMA Infoday - 23 May 2011 1
5757
Scientific Advice (paediatric only)
57
SA +PA
Paed
%2007 281 7.5
2008 320 7.2
2009 388 7.7
2010 400 8
0
5
10
15
20
2007
2008
2009
2010
58
PDCO AchievementsPDCO 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
60