“5th anniversary Paediatric Regulation”
PDCO Achievements
Daniel Brasseur
PDCO
European Medicines Agency
An agency of the European Union
Paediatric Regulation
2
2
Take home message
Good research in children is a need &
time is needed to develop good research
3
Research Needs in Paediatric Medicines
Total Opinions (+&-)
4
700
Research Needs in Paediatric Medicines
5
PIP Opinions (= need)
500
Total Opinions
700
Research Needs in Paediatric Medicines
PIP Opinions (= need)
500
Total Opinions
700
70% out of 700
6
7
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
8
Overview of PDCO Procedure
Adoption of
Opinion,
or
Adoption
of
Opinion
&
Final Report
Request for
Modification
Start
Clock
60 DAYS
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Stop
Clock
ReStart
Clock
Opportunity
for the
Company
to introduce
Modifications
60 DAYS
Decision
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision
9
9
Overview PDCO of Procedure
Adoption
of
Opinion
&
Final Report
Adoption of
Opinion,
or
Request for
Modification
Start
Clock
60 DAYS
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Stop
Clock
ReStart
Clock
Opportunity
for the
Company
to introduce
Modifications
60 DAYS
Decision
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision
10
10
Overview PDCO of Procedure
Adoption
of
Opinion
&
Final Report
Adoption of
Opinion,
or
Request for
Modification
Start
Clock
60 DAYS
Understand Plan
Detect Problems
Identify Experts
Propose Changes
Stop
Clock
ReStart
Clock
Opportunity
for the
Company
to introduce
Modifications
60 DAYS
Decision
Evaluate Changes
Find Agreement
Finalize Plan
Publish Decision
11
11
12
13
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
14
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
Poland
Portugal
Romania
Slovenia
Spain
Sweden
The Netherlands
United Kingdom
Hungary
Icelan
Ireland
Italy
Latvia
Lithuania
Luxembourg
Malta
Norway
Patients' Organisation
Austria
Belgium
Bulgaria
Czech Republic
Denmark
Estonia
Finland
France
Germany
Healthcare and Academia
Rapporteurships
70
60
50
40
30
20
10
0
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
EMA
Sm Report
Day 1
17
Peer
Reviewer’s
Comments
Day 27
Members’
written
Comments
Day 30-55
Update EMA/
PDCO Report
Request for
Modification
Re-Start
Clock
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
EMA
Sm Report
Day 1
18
Peer
Reviewer’s
Comments
Day 27
Members’
written
Comments
Day 30-55
Update EMA/
PDCO Report
Request for
Modification
Re-Start
Clock
PIP Procedure Second step = 9 “expert” inputs
OE?
Company’s
PIP ReSubmission
Day 61
EMA
Sm Report
Update
Day 71
2nd Rapp & 2nd PDCO
Oral
Discussion
Present.
+OE?
Day 90
.
3rd PDCO
Discussion
Final Report
Day 120
PDCO
Opinion
Re-Start
Clock
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
19
Final EMA
Decision
Day 130
EMEA
Decision
20
20
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
21
Applications assessed by FWG
PIPs reviewed by Quality Sector
Around 1000 PIPs
validated PIP/waiver
applications
250
220
200
(March 2011)
150
60%
15/m
100
50
No. of PIPs
84
54
0
2008
22
2009
2010-2011
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
Regulatory references 2
(Draft) Guideline on pharmaceutical development of medicines for
paediatric use
24
•
Collaborative work between QWP, PDCO, and external experts.
•
Public consultation aimed very soon.
25
26
WGroups
Non-Clinical
Start
Clock
DAY 0 or 30
Opportunity
to discuss need for
juvenile animal
studies
27
Stop
Clock
ReStart DAY 60 or 90 Opinion
Clock
Opportunity
to discuss need for
juvenile animal
studies
28
ay
-0
9
ar
-0
9
ay
-1
0
ar
-1
0
ay
-1
1
ar
-1
1
Ju
l-1
1
Se
p11
M
M
Ja
n11
No
v10
Ju
l-1
0
Se
p10
M
M
Ja
n10
No
v09
Ju
l-0
9
Se
p09
M
M
Ja
n09
No
v08
Number of PIPs discussed
NcWG discussions November 2008 - September 2011
25
20
15
Re-discussions
New PIPs
10
5
0
WGroups
Methodology
Start
Clock
DAY 0 or 30
Opportunity
to discuss
extrapolations
statistics
?modelling
29
Stop
Clock
ReStart DAY 60 or 90 Opinion
Clock
Opportunity
to discuss
extrapolations
statistics
?modelling
No
Reasonable to assume equivalence
of disease Children = Adults
- similar progression?
- similar response to intervention?
Yes
Yes
Reasonable to assume similar
concentration response (C-R)
in Children = Adults?
Conduct PK studies
Conduct S & E trials
No
No
Is there a PD
measurement
that can be used
to predict E?
Yes
Conduct PK studies
to achieve levels
similar to Adults
Conduct S trials
Yes
Conduct PK/PD studies to get CR for PD measurement
Conduct PK to achieve target concentration based on CR
Conduct S & E trials
30
Methodological constraints in small populations
Overall population
Prevalence
Affected population
Diagnosis
Sick population
(patients)
Project
Available Population
(volunteers)
Participating
Population
(Cases)
CT
31
“Classical Power”
Resources
Protocol
Modelling and Simulation!
32
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
33
34
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
35
36
60%
37
38
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?
39
6%
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
40
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
An agency of the European Union
Results (I)
Most frequent medicines used off-label/ unauthorised:
– antiarrhythmics,
– antihypertensives (rennin-angiotensin inhibitors and betablockers),
– 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.
42
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)
43
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.
44
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
45
46
List
Applicant’s
project
DG
Research
evaluation
Funding
DG Research
EMA
PDCO
evaluation
47
PIP
List
Applicant’s
project
DG
Research
evaluation
Funding
DG Research
EMA
PDCO
evaluation
48
PIP
List
Applicant’s
draft PIP
PDCO
DG Research
EMA
PIP
49
List
PDCO
Funding
DG Research
EMEA
PIP
Applicant’s project
+ agreed PIP
50
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
51
Academia
Researcher
Regulators
HCP
Industry
52
PDCO Achievements
Plan
Implementation of procedures
PIP Evaluation and Outcomes
Survey of the Needs
Priority list & FP7
Enprema
Challenges
53
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
54
EFPIA/EMA Infoday - 23 May 2011
1
34 companies provided input
biologicals
55
EFPIA/EMA Infoday - 23 May 2011
6
Timing of Art.7 PIP submissions for new
medicinal products (information received on N=146 out of 168 submitted PIPs)
56
EFPIA/EMA Infoday - 23 May 2011
1
Scientific Advice (paediatric only)
SA Paed 20
+PA
%
15
2007 281 7.5
2008 320
7.2
10
2007
2008
2009
2010
5
2009 388
7.7
FU
PA
PA
ed
ed
Pa
ed
Pa
Pa
57
Pa
SA
SA
8
ed
2010 400
FU
0
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
58
Take home message
Good research in children is a need &
time is needed to develop good research
59
60