opportuniesandpi/allswhen, measuringharmreduconthrough ... · if,the,aimof pharmacovigilance,is,...

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

Disclosure statement

No conflicts of interest to declare

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

Impact pharmacovigilance depends on whether knowledge reaches health care

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

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






usage


Es?ma?ng

Defini?on impact


Defini)on impact

Reduced number of venous thromboembolism before and a_er 2013 in women childbearing age


Safety signal

Health care ac?ons

Regulatory ac?on

Rela?ve risk






usage

Defini?on impact



Es?ma?ng


usage





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



Rela?ve risk




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






usage

Defini?on impact

Assessing the change on health

Es?ma?ng

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




Project Impact PV

Safety signal

Health care ac?ons

Regulatory ac?on

Rela?ve risk



Scheme of assessment




usage

Defini?on impact



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






Es?ma?ng

Defini?on impact


Defini)on impact

Reduced number of cardiac valvulopathy in Parkinson pa?ents before PV ac?vi?es (2003) and a_er

(2013)


Safety signal

Health care ac?ons

Regulatory ac?on

Rela?ve risk






usage

Defini?on impact



Es?ma?ng

Rela?ve risk






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






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






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






usage

Defini?on impact

Assessing the change on health

Es?ma?ng


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!




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




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




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

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