Update on the Standard EudraVigilance Paediatric Query Paediatric - PowerPoint PPT Presentation

Update on the Standard EudraVigilance Paediatric Query Paediatric workshop – 28 April 2014 Presented by: Cosimo Zaccaria Signal Management – Pharmacovigilance Department An agency of the European Union

– Safety in the Special population – PhV obligations – EudraVigilance overview – Paediatric queries – Future implications and usefulness of EV paediatric queries – Conclusions 2 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

I ntroduction • Paediatric population: age < 18 y/ o • Pregnant women • Elderly population • Population with genetic conditions • Groups with specific disease • Etc… W ould the presence of this special condition alter the effects of the drug producing m ore or different adverse events? 3 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Off-label use of m edicinal products in children Use in children despite a relative lack of information on how to prescribe safely: • Dosing error – medication error • More severe ADRs or different from what is known in adults. • Higher underreporting in children vs adults • Risk/ benefit balance in children could change 4 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

How to im prove the health in children • Increase high quality, ethical research into medicines for children • Increase availability of authorised medicines for children • Pharmacovigilance : Improve Paediatric Signal Detection • Increase inform ation on medicines Achieve the above: W ithout unnecessary studies in children 5 5 Development of medicines for children: the EU experience Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

The EU Paediatric Regulation 1 9 0 1 / 2 0 0 6 New obligations for Pharm acovigilance : it is essential to ensure that PhV mechanisms are adapted to meet the specific challenges of collecting safety data in the paediatric population, including data on possible long- term effects. 1 . Obligations for new applications ( PI P/ w aivers/ Deferrals) 2 . Obligations for approved products: Article 4 5 & 4 6 aiming at not repeating studies that have previously been performed. Impact in reducing ADRs Main aim : im prove paediatric health w ithout delaying authorization for adults 6 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Monitoring of drugs in the paediatric population Pharmacovigilance 1 ) Standard Paediatric query 2 ) Paediatric Signal Detection 7 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Post-Authorisation reports ( I CSRs) : EVPM Children: 249 .776 9 8 % – - Adult: 3.094.729 9 3 .5 % Clinical Trial reports ( SUSARs) : EVCT Paediatrics: 6.684 2 % – - Adults 216.164 6 .5 % Paed. EVCT overtim e Paed. EVPM overtim e 1200 70000 60000 1000 50000 800 40000 600 30000 400 20000 200 10000 0 0 8 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Children vs Adults TOTAL EV = ~ 4 .5 m illion I CSRs Tot I CSRs by EEA Country 9 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Access Policy – external requests • Written requests (including emails) for access to any document originated, received or held by the Agency • Proactive disclosure of EMA documents through website or other sources • Protection of commercial and confidential information, personal data and conflicting interest+ 10 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Standard EV paediatric query – internal requests “General” standard EV paediatric query ( routine) – any evidence of the rum our in the paediatric profile reported in EV in the paediatric population? – any differences as com pared to the adult population ? – any specific paediatric age group at risk taking in account the progressive m aturation of the organ involved? “ Detailed “standard EV paediatric query ( ad hoc query) – issue specific to the product/ substance or exists for the all class ? – role of the specific form ulation (s) used in the paediatric population? – any specific paediatric age group at risk taking in account the progressive maturation of the different functions of the organ involved – Any other paediatric specificities ? Dose? Duration? I ndication? … (ad hoc) 11 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

General Standard EV Paediatric Query ( SEVPQ) triggered by PDCO START Additional Ad hoc analysis A query on EV database is needed: analysis of the role requested by of formulation , class, sex, PDCO/PaedTeam dose, indication etc. Timelines to be defined case General Standard EV by case according to Paediatric issue Query’ is complexity and seriousness of paediatrics the issue generated Within 15 days as standard Conclusion presented to is theSafety concern PDCO/PRAC yes statistically reflected in EV ? paediatrics no END 12 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Request of a Standard EV paediatric query Tem plate for internal request 13 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

General Standard EV paediatric query 1 . I ntroduction 1. Description of the safety concern 2 . Query results 2.1 General paediatric ADR profile for the product/ active substance 2.2 Analysis of the specific issue in the paediatric population 2.3 analysis of the specific paediatric issue per age group 3 . Sum m ary and conclusions Confirmation whether the risk is reflected or not in EV 4 . Annexes 14 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Standard Paediatric Query since 2 0 1 0 7 out of 9 reports reflected the risk in EV 1. Captopril & nephrotoxicity – reflected in EV Pilot phase 200 9 -2010 2. Cisplatin & Ototoxicity - reflected in EV 3. Gadobutrol & Nephrogenic System ic Fibrosis - not reflected 201 1 4. Metoclopramide & Neurotoxicity - reflected in EV 5. Fenofibrate & Rhabdom yolysis - not reflected 201 2 6. Terbinafine & haem atopoietic cytopenias – reflected in EV 7. Previgen & haemolytic disorders - reflected in EV 201 3 8. Enalapril & Renal and Cardiotoxicity - reflected in EV 9. Captopril & Renal Cardiotoxicity – reflected in EV 15 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Captopril and Renal Toxicity as an example I ntroduction 1. Basic information Captopril is an ACE inhibitor used for the treatment of hypertension and some types of congestive heart failure. Nephrotoxicity is an adverse reaction already recognized in adults for Captopril. 2. Information on the known safety profile Adverse effects of Captopril include cough, angioedema, agranulocystosis, proteinuria, hyperkalemia, taste alteration, teratogenicity, postural hypotension, acute renal failure and leukopenia 3. Uses in children Experience with Captopril in children is limited. The BNFC refers to the use of captopril in hypertension, heart failure, proteinuria in nephritis , or diabetic nephropathy. 16 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Captopril and Renal Toxicity as an example 1 . Graph com paring the num ber of paediatric and non- paediatric cases: 2 . Num ber of Paediatric ADRs by I CH E1 1 age group categories 17 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Captopril and Renal Toxicity as an example 3 . General paediatric profile per SOC versus Adult ADRs: 18 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Captopril and Renal Toxicity as an example 4 . Statistical analysis : Paediatric PRR ratios at SOC level ‘ Renal and Urinary Disorders’ PRR-ratio statistic 1 : children vs. adult based on all cases reported for Captopril Captopril cases for SOC 'Renal and urinary disorders' in children 3 1 / Captopril cases in children 1 0 1 -------------------------------------------------------------- Captopril cases for SOC 'Renal and urinary disorders' in adult 1 2 2 / Captopril cases in adult 9 3 6 Ratio= 2 .3 5 CI 1 .6 8 - 3 .3 0 PRR-Ratio statistic 2 : Captopril vs. all other products based on paediatric cases only Captopril paediatric cases for the SOC 'Renal and urinary disorders' 3 1 All Captopril paediatric cases 1 0 1 ---------------------------------------------------------------------- All other drugs paediatric cases for the SOC 'Renal and urinary disorders' 7 1 4 1 / All other drugs paediatric cases 2 1 7 9 9 8 Ratio = 9 .3 7 CI 6 .9 8 – 1 2 .5 7 19 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

Stratification by Age according to the organ m aturation Number of cases by ICH E11 Age group in Children for the SOC 'Renal and urinary disorders' 12 11 10 10 8 8 Number of cases 6 4 2 2 0 0 - 28 days >28 days - 24 >24 Months - >12 - 18 Months 12 Years Years Number of cases by Specific Age Group in Children for the SOC 'Renal and urinary disorders' 20 18 18 16 13 14 Number of cases 12 10 8 6 4 2 0 0 - 36 Months days >36 Months - 18 Years 20 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department

General Standard EV paediatric query 4 . Sum m ary and conclusions 21 Cosimo Zaccaria - Signal Management – Pharmacovigilance Department