an agency of the european union daniel brasseur pdco european medicines agency “5 th anniversary...

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

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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