läkemedelsverkets farmakovigilansdag 2017-05-30 · läkemedelsverkets farmakovigilansdag...

Läkemedelsverkets farmakovigilansdag 2017-05-30

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PRAC : Pharmacovigilance Risk Assessment Committee

Kommittén för säkerhetsövervakning & riskbedömning av läkemedel

Farmakovigilansdagen maj 2017Ulla Wändel Liminga, PhD

Ämnesområdesansvarig farmakologi/toxikologi; PRAC‐ delegat 1

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• The PRAC• Structure, responsibilities and tasks• Transparency • Five year of PRAC work – some figures

• Recent referral procedures – examples

• PRAC Workplan 2017

Summary of presentation



1 Member/Member State (n=28)1 Alternate/MS 1 Member fr Iceland, Norway6 Independent experts nominated by EC1 + 1 Health care professional (EC & EP)1 + 1 Patient organisation (EC & EP)

Chairperson: June Raine (UK)

Vice Chair: Almath Spooner (Ireland)

The PRAC

SE: Ulla Wändel LimingaQun‐Ying Yue (alternate)Charlotte Backman (co‐ordinator)

Nominated by EC – European Commission; EP European Parlament

4 days meetings, 11 times / year

PRAC responsibilities and tasks

All aspects of safety and risk management

• Detection, assessment, minimisation, communication risk for adverse reactions, while taking therapeutic effect into account – Union procedures (referral) related to safety (Art. 20, 31, 107)

– PSUR (Periodic Safety Update Report); EURD

– Signal assessment; Additional monitoring list

– Risk management plans

– Non‐interventional safety studies (PASS; design, report)

– Pharmacovigilance audit; PhV inspections

– Recommendation/advice on safety to CHMP, CMDh, EMA, European Commission e.g. renewals, selected Type II variations

– Functionalities of Eudravigilance, PSUR repository

All centrally authorised products; selected issues for non‐centrally authorised products

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PRAC ‐ transparency• Publication of PRAC documents

– Agenda

– Highlights

– Minutes

– Questions to MAHs, time tables for referral procedures

– Referral assessment reports

– Monthly list of signals discussed etc; MAH to monitor

• Stake holders can submit information in some procedures

• Possibility for public hearings

– first one planned in valproate referral; autumn 20175

Five years of PRAC ‐ some figures

• 44 referrals from 2012‐2017 e.g.– Combined oral contraceptives – risk for VTE, ATE

– Diclofenac – cardiovascular safety

– HES – hydroxy ethyl starch – serious risks in sepsis/critically ill patients

– Retinoids ‐ risks use in pregnancy, psychiatric events

– Valproate (twice) ‐ risks use in pregnancy

– Gadolinium contrast agents – brain deposition

– Paracetamol modified release ‐ handling of overdose

– Gardasil – POTS and CRPS

• Many PSURs, RMPs, renewals….In 2016 – PSUSA : 796 (205 plenary)

– RMP : 550 (159 plenary)

• ~ 340 signals, 574 signal discussions (~12 / month) 2012‐ 2016 6



PRAC Workload 2012 – 2015

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Referral procedures started at PRAC by triggering party per article from July 2012 – End 2016

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Total 44 R/CoRSE : 3/ 8UK: 9/7DE: 6/6NL 6/5



Update of PI49%

Routine PhV / monitor

within PSUR35%

Ongoing within signal procedure

6%

Ongoing within

PSUSA/PSUR procedure

3%

Referral evaluation

5%

Update of RMP1.8%

PASS0.6%

Signals at PRAC 2012-2016

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Recent referrals

• Tysabri (natalizumab) :– PML and Risk management ‐ February 2016

• Inhaled corticosteroids :– no difference in risk for pneumonia between products‐March 2016

• Fusafungine – withdrawn due to serious allergic reactions & limited evidence of benefit Feb 2016

• SGLT2– minimise the risk of diabetic ketoacidosis ‐May 2016

– toe amputations – revised product information ‐ Feb 2017

• Direct‐acting antivirals for hepatitis C– Screen for hepatitis B to address risk for reactivation + further studies in relation to

potential risk for early recurrence of hepatic cancer – December 2016

• Zydelig – risk management of serious infections – October 2016

• Factor VIII ‐ plasma derived and recombinant products – Inhibitor development – updated product information – May 2017



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Valproate – referral 2014 • Intra‐uterine exposure to valproate associated with increased risk of

developmental disorders in offspring; known risk of congenital anomalies confirmed.

• Valproate not be used in female children, women of childbearing potential & pregnant women unless alternative treatments ineffective or not tolerated in various epileptic seizure indications, manic episode in bipolar disorders, while contraindicated as prophylaxis of migraine attacks

• Further changes to product information

• Educational materials to better inform patients & healthcare professionals

• DHPC – neurologists, psychiatrists, general practitioners, obstetricians/ gynaecologists, family

planning centres, pharmacists, health visitors, midwife, school nurses

• Drug utilisation study

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Valproate – thereafter

• Drug utilisation surveys shown that knowledge about these risks not communicated

• Further actions taken by someNCAs (e.g. France, UK)– DHPC sent again in SE 2016

• New referral started 2017

• How get messages across ?? – General question for all communication on safety of medicines ….



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Retinoids‐ referral 2016/2017

• EU‐review started in July 2016 following review of data on effectiveness of pregnancy prevention programmes (PPP) for oral isotretinoin– Data raised concerns on how PPP followed in practice; and

inconsistencies between products

• Same challenges – how can messages get across ??

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Paracetamol modified release 2016/2017

• Review B/R of paracetamol modified & prolonged‐release tablets [MR]; immediate release [IR] not included in review

• Standard procedures for handling paracetamol overdose & poisoning designed for IR products

• Case reports & retrospective PK & clinical analysis* indicate that recommended risk assessment of suspected poisonings and standard treatment protocol with antidote N‐Acetylcysteine, insufficient to manage overdoses with Alvedon 665 mg MR– exposure profile following overdose and subsequent clinical course unpredictable

– absorption prolonged, maximal plasma concentrations observed later than expected from overdoses IR paracetamol

– Cases of overdose with Alvedon 665 mg modified release tablets causing hepatic injuries, despite timely treatment, have been identified

• Review is ongoing. BE PRAC Rapp, SE PRAC CoRapp.

* Salmonson H, et al. Clin Toxicol 2016;54:424 (Abstract 124)



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Gadolinium contrast agents for MRI (GdCA)

• Mar 2016 : Start of referral on Gd contrast agents for MRI to review risk of Gd deposition in brain tissue

• Mars 2017 : PRAC recommends regulatory actions:

– Suspension of four linear Gd contrast agents

– Primovist (for hepatic MRI) remains with SmPC updates

– Product information for other (macrocyclic agents) to be updated

• April 2017: Some MAHs have requested a re‐examination

– Re‐examination started in May; expected to conclude in July 2017

– SE (UWL) PRAC rapp; DE PRAC CoR

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Gd: Summary grounds for PRAC recommendation Mar 2017

• Data (stability, in vitro, non‐clinical) suggest more Gd released from linear than macrocyclic agents

• Gd measured in brain indirectly and directly.

– Non‐clinical data show linear agents persist up to one year / longer. Macrocyclic transient

• No adverse neurological effects demonstrated; long‐term safety data limited

• Harmful effects plausible (dechelation and known toxicity of unchelated Gd).

• Linear GdCAs associated with risk of NSF, Gd‐associated skin plaque

• Studies to fully address serious concerns not feasible

• Risk minimisation measures not effective

• B/R negative for gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide

• B/R positive for

– Primovist (gadoxetic acid) due to substantial hepatic uptake, low dose, clinical utility for some imaging

– Magnevist (gadopentetic acid) for intra‐articular injection

– All macrocyclic GdCAs with SmPC changes



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PRAC Work plan 2017 – 62 activities

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PRAC Work plan 2017 MPA involved in• 1.1.1. Expert input to GVP P.III – on pregnancy – release public consultation

• 1.1.2. Optimise RMP – GVP V on ‘Risk management systems’

• 1.3.1. Task force patients registries

• 1.5.2. Various activities on signal detection incl• Develop strategic approach on signal validation activities by industry

• 1.5.3. Impact f PhV

• 1.6.1. Regulatory science (pharmacogenomics)

• 2.5 Process improvements • Content & process of PSURs/PSUSA; Initiate revision of GVP VII on PSUR

• Better guidance for assessors to facilitate publication of PSUR AR

• Support GPAG (reviews EURD list – on dates for PSUR submission)

• Implement & operate new format of GVP V on RMP

• Review quarterly workload & performance measures

• Support established PRAC WG on efficiency & effectiveness plenary meetings

• Expert advice on optimal role of PRAC for safety related variations



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PRAC Work plan 2017 ‐ examples

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Wrap up and ?

• Variety of issues handled by PRAC • Risk management and risk communication• Impact of pharmacovigilance• Work load and capacity

• Brexit …

läkemedelsverkets farmakovigilansdag 2017-05-30 · läkemedelsverkets farmakovigilansdag...

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