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

Paediatric Regulation 2

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

Research Needs in Paediatric Medicines Total Opinions (+&-) 700

Research Needs in Paediatric Medicines PIP Opinions (= need) 500 Total Opinions 700

Research Needs in Paediatric Medicines PIP Opinions (= need) 500 Total Opinions 700 70% out of 700

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

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

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

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

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

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

Rapporteurships

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

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

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? 90 . 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

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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

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

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 Collaborative work between QWP, PDCO, and external experts. Public consultation aimed very soon.

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

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

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

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

Modelling and Simulation!

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

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

60%

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%

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

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

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.

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)

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.

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

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

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

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

Applicant’s project + agreed PIP 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

Academia Researcher Regulators HCP Industry

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

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

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

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