Post on 10-Mar-2019
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Florence van Hunsel, Laura Peters, Helga Gardarsdo5r, Agnes Kant PharmD, Epidemiologist, PhD Head Signal Detec?on Lareb
Opportuni)es and pi/alls when measuring harm reduc)on through pharmacovigilance ac)vi)es
If the aim of pharmacovigilance is to reduce harm by more appropriate use of medicines of pharmacovigilance and if we can measure or es)mate the harm which is reduced by PV, we generate evidence about the effec)veness and public health consequences of pharmacovigilance ac)vi)es at popula)on level and show the importance of PV ac)vi)es
Opportunity
Scheme of the pathways of PV
Source: ENCePP Guide on Methodological Standards in Pharmacoepidemiology
Impact pharmacovigilance depends on 1. methods for data collec)on
2. methods for signal detec)on ilance
Pi/alls Ø pharmacovigilance process complex:
different stakeholders and ac)vi)es
Ø PV ac)vi)es are to some extend intertwined and complementary
Ø Data on outcome lacking
Ø Influence other factors on outcome
Project Impact PV Aim project
Ø GeLng insight in the data needed and publicly available for measuring the impact of PV ac)vi)es on health for iden)fied safety risks
Ø Measure or es)mate the impact for these specific safety signals
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Scheme of assessment
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Data on change in health
Es?ma?on the change on health
Es?ma?ng
1. Extensive off label use of Diane-‐35
Correc?on
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Safety signal • Clinical trial: first signs of venous thromboembolisms (VTE). 1987
• ANSM research: large off-‐label use Diane-‐35 (70%). 2013
• Lareb: 309 VTE reports. Large off-‐label use 2013
Rela)ve risk Diane-‐35 vs non-‐users = 3.9
Regulatory ac)on PRAC (and MEB) 2013 • Indica?on = moderate-‐to-‐severe acne and/or hirsu?sm
• Only second-‐line treatment • No use in combina?on other OAC
Health care ac)ons Dutch GP Associa?on (NHG): Safety warning: Only prescribe Diane-‐35 for acne and/or hirsu?sm. 2013
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Es?ma?on the change on health
Es?ma?ng
Defini?on impact
Data on change in health
Defini)on impact
Reduced number of venous thromboembolism before and a_er 2013 in women childbearing age
Data on change in health
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Data on change in health
Es?ma?on the change on health
Es?ma?ng
Other factors influencing
usage
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Rela?ve risk
Data on other risk factors Risk factors of venous thromboembolisms: • Obesity, age, smoking • Pregnancy
During the ?me period no significant changes were found in these factors
Data on risk no use and alterna)ves? Alterna?ves increase risk as well • No use: risk of VTE 1.9/10.000 • 3rd gen. HC vs no use: RR: 3.8 • 2nd gen. HC vs no use: RR: 2.8
New users: increased risk of 1.5-‐3x
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Other factors influencing
usage
Change in use of medicine
Diane-‐35 usage decrease of 75% High-‐risk combined oral contracep?ves decrease of 27% Low-‐risk combined oral contracep?ves increase of 6%
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
Diane-‐35 High-‐risk COCs Low-‐risk COCs
Usage of COCs
2010-‐2012 2015
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Assessing the change on health
Es?ma?ng
Es)ma)ng the change on health
Es)ma)ng the change on health
H o r m o n a l contracep?ve
Users before 2013
T h r o m b o ? c cases/year
Diane-‐35 180.000 130 High-‐risk COCs 430.200 310 Low-‐risk COCs 1.419.800 755 Total 2.030.000 1195
Users a_er 2013
thrombo?c cases/year
44.000 32 322.200 233 1.437.800 765 1.804.000 1030
Es?ma?on of prevented venous thrombo?c = 1195 – 1030 = 165 / year
Data on risk of an alterna?ve is lacking !
226.000 less OAC users ! IUD = basic risk VTE
Hormonal IUD (Mirena) users = same risk Low-‐risk COC’s!
Be aware could be overes?ma?on!
Data on new users is lacking!
New users: increased risk of 1.5-‐3x
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Scheme of assessment
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Data on change in health
Es?ma?on the change on health
Es?ma?ng
2. Cardiac valvulopathy -‐ pergolide
Correc?on
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Safety signal • Case-‐reports on 3 severe cardiac valvulopathy. 2002
• Lareb: 3 cases of HVR. 2003
Rela)ve risk Two cohort studies: 2007 Risk assessment: RR of pergolide vs other
an?-‐Parkinson medicine = 3.05
Regulatory ac)on MEB: second-‐line treatment. 2005 CHMP and MEB (2007): • Maximum dosage = 3mg/day • ECGs prior to treatment and
ECG every 6-‐12 months • Contra-‐indica?on for pa?ents
with history of fibro?c reac?on
Health care ac)ons Change guidelines HCP 2007 • Maximum dosage • ECG prior to treatment and ECG
every 6-‐12 months. If risk valvulopathy: stop treatment
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Es?ma?on the change on health
Es?ma?ng
Defini?on impact
Data on change in health
Defini)on impact
Reduced number of cardiac valvulopathy in Parkinson pa?ents before PV ac?vi?es (2003) and a_er
(2013)
Data on change in health
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Data on change in health
Es?ma?on the change on health
Es?ma?ng
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Data on other risk factors
Data on risk no use and alterna)ves Bromocrip?ne: similar working mechanism, but not high risk of fibro?c reac?on in heart valve Other an?-‐Parkinson medicine also no increased risk
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Other factors influencing usage
Regulatory ac?ons in the same ?me period: • Levodopa proven not to further worsen
progression of Parkinson’s disease. 2006 • Compulsive disorder associated with Pramipexol.
2008
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Change in use of medicine Pergolide: 34.048 users (2003) to 4133 users (2013) Other an?-‐Parkinson medicine u?lisa?on changed as well
Rela?ve user numbers of an?-‐parkinson medicine
0
20
40
60
80
100
120
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
An?cholinergic Levodopa Amantadine Pergolide
Bromocrip?ne non-‐ergot DA agonist MAO-‐B inhibitor COMT inhibitor
Safety signal
Health care ac?ons
Regulatory ac?on
Rela?ve risk
Data on other risk factors?
Data on risk no use and alterna?ves?
Data on change in use of the medicine or other safety measurements
concerning the use of the medicine
Other factors influencing
usage
Defini?on impact
Assessing the change on health
Es?ma?ng
Es)ma)ng the change on health
34,048 – 4133 = 29,915 less pergolide users Risk of valvulopathy with pergolide = 16.1% = 4,816 cases Risk of valvulopathy without pergolide = 6.9% = 2,064 cases 4,816 – 2,064 = 2,752 Parkinson pa)ents less at risk for valvulopathy
Risk assessment Risk large varia?on in studies Controls groups not clear
We selected a meta-‐analysis (but s?ll small numbers) : RR of pergolide vs other
an?-‐Parkinson medicine = 3.05
Be aware large varia?on RR in literature!
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Ø The large gap in this assessment is the lack of data on hypomagnesemia cases in the Netherlands
Ø PPIs in NL available OTC -‐> no access to data on change in u)liza)on Ø Other contribu)ng factors that contribute to the risk of developing hypomagnesemia, e.g. renal func,on, alcoholism, gene,c varia,on, metabolic abnormali,es, concomitant medica,on use (loop diure,cs, and an,bio,cs), age, and dura,on of PPI use
Proton Pump Inhibitors (PPI's) and the risk of
hypomagnesaemia
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Ø Not possible to assess the Health outcome with publically available data Ø The studies examining the risk agree that there is a lack of methods to assess the number of CV events while using medicines
Ø Varying results of the studies à difficulty in choosing RR for impact es)ma)on Ø We only assessed PV ac)vi)es within Europe, but many more drug warnings and relevant publica)ons could have influenced the u)liza)on of RZG. For example, the publica)on of Nissen and Wolski (2007).
Rosiglitazone withdrawal due to cardiovascular effects
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Assessment of iden)fied safety risks:
1. Extensive off label use of Diane-‐35 (cyproterone/ethinyloestradiol) and thrombo)c risk
2. Pergolide, cabergoline, bromocrip)ne and the risk of cardiac valvulopathy 3. Proton Pump Inhibitors (PPI's) and the risk of hypomagnesaemia 4. Rosiglitazone withdrawal due to cardiovascular effects 5. Progressive Mul)focal Leukoencephalopathy (PML) as a side-‐effect off natalizumab 6. Valproate and the risk of developmental disorders in children exposed in-‐utero
Project Impact PV
Ø Two Dutch databases available, containing data on health of infants exposed to valproate in utero: EURAP and pREGnant.
Ø They have a small cohort of approximately 5% (n=150) of all pregnant VPA users per year and register al congenital malforma)ons.
Ø In NL u)liza)on gradually decreased over the past decade and the safety signal did not affect the u)lisa)on in the Netherlands at large.
Ø No info on developmental disorder, only congenital anomalies
Valproate and the risk of developmental disorders in
children exposed in-‐utero
Ø It is important to define clearly which health effect/outcome to measure in which )meframe in which target group
Ø Therefore an assessement of the safety signal is needed
Ø Publicly available data on health outcomes in the NLs are olen lacking à use of registers/databases some)mes necessary!
Ø Es)ma)on of the impact is possible based on data of the RR and change in use
Closing remarks
Ø Data on use are on popula)on based, and mostly not explicit for the target group and some)mes lacking for the )me period
Ø It is important to take into account alterna)ve use
Ø The RR in literature can be conflic)ng: what to choose?
Ø It is important to take into account other factors àffec)ng the outcome
Ø Feasibility study! Other datasources + study methods possibly more appropriate
Closing remarks
Ø Pharmacovigilance Risk Assessment Commipee (PRAC). PRAC Strategy on Measuring the Impact of Pharmacovigilance Ac)vi)es (Rev 1) (EMA/165407/2017) [Internet]. 2017 Available from: hpp://www.ema.europa.eu
Ø Goedecke T, Morales DR, Pacurariu A, Kurz X. Measuring the impact of medicines regulatory interven)ons -‐ Systema)c review and methodological considera)ons: Methods for measuring impact of medicines regulatory interven)ons. Br J Clin Pharmacol. 2018 Mar;84(3):419–33.
Ø ENCePP Annex 2. Guidance on methods for pharmacovigilance impact research
More informa)on