Pharmacovigilance in 2018 24 September 2018 Twelfth - PowerPoint PPT Presentation

Pharmacovigilance in 2018 24 September 2018 Twelfth Pharmacovigilance Stakeholder Forum Dr Peter Arlett Head of Pharmacovigilance and Epidemiology Department EMA An agency of the European Union

Headlines 1. EU pharmacovigilance supports safe and effective use of medicines 2. EU pharmacovigilance supports patients to get new products 3. EU pharmacovigilance legislation fully implemented 4. New EudraVigilance system launched November 2017: detects safety issues earlier 5. Robust assessment supports rapid effective action on safety issues 6. Enhanced engagement with users of medicines 7. Driving process improvement through regulatory science 8. Starting to realise the potential of real world evidence 9. Challenges: new data, new technology 10. Challenges: making an impact through change in healthcare practice 1

In this presentation… … • Reminder: our shared objective • Focus on product benefit risk • Focus on public engagement • Focus on pharmacovigilance processes • Focus on new data and new science • Don’t forget the people • Challenges and opportunities 2

Reminder: our shared objective… … To promote the health and wellbeing of EU citizens, through optimisation of the safe and effective use of medicines • Underpinned by robust science, efficient processes and excellent people • Manage benefit risk through the lifecycle of products • Go beyond regulation: bringing together stakeholders to deliver innovation safely 3

… ..to understand how the pharmacovigilance system works… .. Santoro et al 2017 Drug safety 40: 855-869

Focus on product benefit risk A few examples of benefit risk action taken at EU level… … 5

CAR-T cell products Kymriah and Yescarta authorised for leukaemia / lymphoma: intensive PRIME support including registry 6

September PRAC - 4 signals required letters to healthcare professionals Rivaroxaban ( XARELTO) Sildenafil ( REVATI O, • Increased mortality, bleeding VI AGRA) and clots in patients treated • Pulmonary hypertension & death for trans-catheter aortic valve in infants exposed in utero • Clinical trial in growth replacement (off label) retardation (off label) 1 3 / 0 8 / 2 0 1 8 - EMA notified that trial suspended 1 4 / 0 8 / 2 0 1 8 – EU I ncident Managem ent Netw ork 2 7 / 0 7 / 2 0 1 8 - EMA notified that trial suspended teleconference 0 5 / 0 9 / 2 0 1 8 – PRAC agrees letter w arning to 0 5 / 0 9 / 2 0 1 8 – PRAC agrees letter w arning to professionals professionals Hydrochlorothiazide Fluoroquinolones • Risk of lip and non-melanoma skin cancer Risk of aortic aneurysm and dissection 1 2 / 2 0 1 7 - Tw o Danish 2 0 1 5 -2 0 1 8 - Epidem iological and epidem iological studies non-clinical studies published 0 5 / 0 9 / 2 0 1 8 – PRAC agrees letter Q1 2 0 1 8 EMA w arning to professionals epidem iological study 0 5 / 0 9 / 2 0 1 8 – PRAC agrees letter w arning to professionals

Dolutegravir (Tivicay): treatment for HIV infection Cases of neural tube defects from observational study of use in Botswana 7/ 5/ 18 EMA informed of study result by WHO and company 17/ 5/ 18 PRAC agreed letter warning professionals not to use dolutegravir in women planning a pregnancy and that women of child bearing potential who take dolutegravir should use effective contraception 18/ 5/ 18 Coordinated press-releases from EMA, FDA and WHO with consistent warnings 8

Daclizumab beta (Zinbryta): treatment for multiple sclerosis Spontaneous reports from a neurology centre in Germany of encephalitis and death 2 0 / 2 / 1 8 EMA informed by PEI 23/ 2/ 18 EU Incident Review Network teleconference recommends referral to PRAC 1/ 3/ 18 MAH informs of intention withdraw the marketing authorisations 6 / 3 / 1 8 PRAC recommends benefit risk negative with suspension of the product and recall to pharmacy and hospital level + letter to warn professionals 9

Focus on public engagement … core of this mornings sessions… . 10

11 Presentation title (to edit, click Insert > Header & Footer)

Public Hearing: quinolone and fluoroquinolone medicines 12

13

Research: listening to the public 14

Focus on pharmacovigilance processes 15

A landmark paper on EudraVigilance … Around 50% signals derive from Eudravigilance ICSRs Other sources - PSURs - RMPs - post-authorisation safety studies - published literature > 54% serious safety issues detected earlier if EV used in addition to other resources Alvarez Y et al 2010 Drug Safety 33(6) 475 -87

Sep 2 0 1 2 – Jun 2 0 1 8 Median: 12 774 signal discussions per month 453 signals * Dashed line – 2018 estimate based on Q1Q2 18

19

Signal detection pilot – extension of the pilot through 2019 20

RMPs: deliver proactive planning of risk minimisation and data collection 21

Pharmacovigilance referrals 22

Finalised and ongoing pharmacovigilance referrals 2018 YTD Procedure nam e I NN Article Start date Finalised Retinoids acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tretinoin, tazarotene 31PhV Jul-16 Mar-18 nalidixic acid, pipemidic acid, cinoxacin, enoxacin, pefloxacin, lomefloxacin, Quinolone and 31PhV Feb-17 Ongoing ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, norfloxacin, prulifloxacin, rufloxacin, fluoroquinolone flumequin Valproate valproate 31PhV Mar-17 Mar-18 Flupirtine flupirtine 31PhV Oct-17 Mar-18 Hydroxyethyl starch hydroxyethyl starch 107i Oct-17 Jun-18 ( HES) Xofigo radium Ra223 dichloride 20PhV Dec-17 Jul-18 Esm ya ulipristal acetate 20PhV Dec-17 May-18 Zinbryta daclizumab 20PhV Mar-18 May-18 Methotrexate oral methotrexate 31PhV Apri-18 Ongoing form ulations 23

Rapporteurs appointed on referrals from Jul. 2012– End Jun 2018 AT, 1 BE, 2 CZ, 2 UK, 11 DE, 7 SE, 4 DK, 2 ES, 5 PT, 6 FR, 2 0 HU, 2 IE, 1 NL, 7 IT, 1 24

PSURs: benefit risk assessments result in direct updates to product information – faster warnings to patients 25

PASS: delivering high quality evidence on the safety of medicines 26

Focus on new data and new science 27

Regulators in-house studies 2013-2017 multiple EMA in- Association betw een system ic house RWD studies to fluoroquinolone exposure and tendon support Committees (mainly rupture: population-based nested case- PRAC) 46 – THIN (UK EHRs) control study 29 - IMS FR/ DE Association betw een hydrochlorothiazide exposure and skin cancer: a series of population-based case-control studies 28

EMA-funded studies N N EMA-funded studies databases countries A/ H1 N1 pandem ic vaccines and pregnancy outcom es 1 1 I m pact of risk m inim isation in patients treated w ith rosiglitazone-containing products 2 2 External RWD I sotretinoin and the effectiveness of the Pregnancy Prevention Program m e in Europe 5 3 studies Patterns and determ inants of use of oral contraceptives in the EU 5 3 to support EMA Monitoring the effectiveness of risk m inim isation in patients treated w ith pioglitazone- 3 3 containing products Committees Risk of cardiac valve disorders associated w ith the use of biphosphonates 6 3 (2010-2017) Association betw een anxiolytic or hypnotic drugs and total m ortality 2 2 15 – EMA Metform in use in renal im pairm ent 2 2 externally Study of regulatory com m unication and risk aw areness follow ing the Article 3 1 referral of n/ a 6 Com bined Horm onal Contraceptives in relation to throm boem bolism contracted Characterising the risk of m ajor bleeding in patients w ith Non-Valvular Atrial Fibrillation: non- 9 6 studies interventional study of patients taking Direct Oral Anticoagulants in the EU Study of utilisation of Com bined Horm onal Contraceptives in Europe 3 3 Anti-m icrobial resistance: choice of therapeutic interventions and outcom es for the treatm ent 4 1 of infections caused by MDR Gram negative pathogens Methods and data sources for determ ining long-term effects of drug exposure during n/ a 2 8 pregnancy, w ith application to antiepileptic m edicines I m pact of EU label changes for system ic diclofenac products: post-referral prescribing trends 4 3 I m pact of EU label changes for hydroxyzine products: post-referral prescribing trends 4 3

EU healthcare databases: 2018 characterisation Only 13 member states have electronic health databases considered suitable for regulatory decision making High heterogeneity in data collected or available through linkages and in data quality 30

New EMA framework contracts for real world data and qualitative research: to deliver evidence for decision-making Lot 1: Use of innovative methods to optimise the utility of sparse data to support benefit/ risk assessment Lot 2: Qualitative research Lot 3: Pharmacoepidemiology research – rapid descriptive studies Lot 4: Pharmacoepidemiology research – association studies, including pregnancy and breastfeeding research 31

Steps to support future real world data use Objectives: To define the opportunities and challenges around implementation of a common data model in Europe to support regulatory decision making. Output: To propose guiding principles for the development of Common Data model in Europe including key criteria for validation in the context of regulatory decision making. 32