A regulatory perspective What do I want to know? June M Raine MHRA, - PowerPoint PPT Presentation

A regulatory perspective What do I want to know? June M Raine MHRA, UK 11 December 2017

What does regulator want to know? Regulatory decision-making responsibilities Answering the regulatory questions Accessing decision-relevant data Moving forward …how can we do better? 2

Regulatory decision-making responsibilities Lifecycle benefit risk evaluation I m pact of Signal detection & regulatory action risk m anagem ent 3

Today’s challenge - earlier access to medicines 4

Santoro et al 2017 Drug safety 40:855-869 5

Uncertainties at time of approval Benefit risk in wider clinical use Effectiveness Time to onset of ADR days 0 20 Populations not studied 40 60 80 Rare ADRs 100 120 1 10 100 1000 10000 Long latency ADRs Frequency of ADR 6

Size of clinical database before approval For 2 0 0 new “standard” medicines median total no patients= 1 7 0 8 For orphan drugs = 4 3 8 patients For 84 medicines for chronic use 7 9 .8 % met guidelines (at least 100 patients for 1Yr) Duijnhoven et al PLoS March 2013 7

Important knowledge gaps to be filled Special populations pregnancy paediatrics elderly At risk groups eg immunosuppressed Long term safety 8

Detecting new safety issues in EU Simplified reporting of ICSRs to EudraVigilance and re-routing to MS Improved quality and completeness of Individual Case Safety Report data – better searchability & efficiency Enhanced signal detection and data analysis tools to support signal detection by member states & MAHs Better detection of new or changing safety issues enabling rapid action to protect pubic health 9

Outcomes of signal assessment PRAC Sep 2012 – Jun 2017 Referral Update of evaluation Ongoing RMP PASS 4.3% within 2.2% 0.5% PSUSA/PSUR 1.6% Ongoing within signal procedure 6% Product Information Routine PhVig update & monitor in [PERCENTAGE] PSUR 36% 10

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What do I want to know? How the medicine is being used What is drug exposure Outcomes of interest Background rates of events of interest What is drug attributable risk Has regulatory action minimised risk When will I get the answers 12

Answering regulatory questions - RMPs In the first 5 years after approval, 20.7% of uncertainties identified at approval were resolved 13

Answering regulatory questions - PASS British Journal of Clinical Pharmacology Volume 83, Issue 4, 884-893 14

Answering regulatory questions - RMMs 15

Accessing decision-relevant data Database studies - Eg risk characterisation, investigation of targeted AEs, impact of regulatory action Drug utilisation stu dies - Eg to assess patterns of use, effectiveness of risk minimisation or help plan PASS Registries (prospective cohorts) - Eg assess safety profile, health outcomes in clinical use, consider comparator 16

Strengths and limitations of registries Strengths Limitations • Relevant clinical parameters • Substantial set up & running costs • Natural history of disease • Time consuming to initiate • Standard of care • Medications commonly missing • Patient stratification • ADRs not routinely recorded • RCTs • Co-morbidities missing • Open label studies possible • Data ownership/governance • Capture off label use • Data Quality • Information on high risk groups • If no comparator will limit utility • Patient reported outcomes 17

Patient registries – research ready? Biologics Haemophilia Pregnancy Multiple Sclerosis Blood and Marrow Transplantation 18

Examples of some EU regulatory questions How is Radium 223 used in non- symptomatic or mildly symptomatic metastatic prostate cancer? Is Human Papilloma Virus Vaccine associated with increased risk of fatigue syndromes in adolescent girls? Are risk minimisation measures to reduce harm of exposure to valproate in pregnancy effective? 19

Understanding how medicine is used Establishing extent of concomitant use of Radium 223 and abiraterone plus steroids across EU while urgent safety review is taken forward 20

ADR reports - observed vs expected analysis Maximised SPRT for ME/Chronic Fatigue Syndrome for girls aged 12/13 years (2008-2009) 8 7 Critical value 10% events reported 6 25% events reported 50% events reported 75% events reported Log Likelihood Ratio 5 100% events reported 4 HPV vaccine - 3 chronic fatigue syndrome 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Week of Surveillance 21

HPV vaccine - background rates of CFS 22

Investigating vaccine signal using RWE Donegan et al 2013, Vaccine 31, 43, 4961-7 23

Impact of regulatory action - valproate Developmental disorders up to 30 -40% of pre-school children exposed in utero in addition to 11% risk of birth defects EU referral in 2014 – strengthened warnings and extensive communications Meador et al NEJM 2009 24

Understanding valproate use in member states 25

26 Rate per 10,000 women 10 15 20 25 30 35 0 5 Effect of valproate action in UK Jan - Jun 2010 Jul - Dec 2010 VPA prevalence in females aged 14-45 years Jan - Jun 2011 Jul - Dec 2011 Jan - Jun 2012 Jul - Dec 2012 Jan - Jun 2013 Jul - Dec 2013 Jan - Jun 2014 Jul - Dec 2014 Jan - Jun 2015 Jul - Dec 2015 Jan - Jun 2016 Jul - Dec 2016 Communications Jan - Jun 2017 disseminated

Moving forward – how can we do better? Meaningful evidence Schneeweiss S et al 2016 Valid evidence Clin Ph Ther 100 6 633-46 Expedited evidence Transparent evidence 27

Generating meaningful evidence Rassen J at ISoP Liverpool, 2017 28

Generating timely evidence Example: Has prescribing of codeine in children changed following regulatory action in 2013 ? Common protocol reduces variability due to misaligned definitions, analytical models Makes use of existing regulatory network  Access to high quality electronic health records  Effective allocation of existing resources  Sharing of expertise and data Greater part of EU population in same study Pilot study to gain experience Assessment of data by PRAC in 2018 29

Moving forward – how can we do better? Agree on common goal – timely access to decision-relevant data to achieve measurable public health outcomes Scenario-specific planning for capability to link local or distributed data sources at global level, support rapid cycle analysis Multi-disciplinary teams including regulators, data providers, pharma and academia to work on common data format 30 30

Regulators are ready to support! Pharmacovigilance Risk Assessment Committee 31