Workshop tematico I molti volti della farmacoepidemiologia - Convegno AIE Segnali in farmacovigilanza: conferme e smentite
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Convegno AIE
Bologna, 18-19 marzo 2019
Workshop tematico
I molti volti della farmacoepidemiologia
Segnali in farmacovigilanza: conferme e smentite
delle relazioni causali
Emanuel Raschi
Alma Mater Studiorum – Università di Bologna
emanuel.raschi@unibo.it
Di che cosa parleremo…
Definizione di segnale e fonti di dati
Il ruolo degli studi di disproporzionalità
(why, when, how)
Pancreatite da incretino-mimetici
Tossicità immuno-relate da inibitori del checkpoint
immunitario
Uno rapido sguardo al futuro
Signal definition
“Information that arises from one or multiple
sources (incl. observations and experiments),
which suggest a new potentially causal
association, or a new aspect of a known
association, between an intervention and an
event or set of related events, either adverse
or beneficial, that is judged to be of sufficient
likelihood to justify verificatory action”
Practical Aspects of Signal Detection in Pharmacovigilance
Report of CIOMS Working Group VIII, Geneva 2010
Data sources for signal detection
(drug safety assessment)
SRS
RCT
HCD
(SUSAR)
Data
mining
Social In silico
Literature
(SR/MA)
HCD: healthcare database; RCT: randomized controlled trials; SR-MA: systematic review/meta-
analysis; SRS: spontaneous reporting system; SUSAR: suspected unexpected serious adverse
reactions
Pharmacovigilance and
pharmacoepidemiology
Farmaci di recente
FarmacoVig commercializzazione
SRS Eventi rari
Farmaco/evento
difficilmente tracciabile nei
DB amministrativi
Evento frequente e
FarmacoEpi multifattoriale (es. infarto)
Necessità di quantificare
HCD rischio
Therapie. 2016 Apr;71(2):211-6
HCD: healthcare database
SRS: spontaneous reporting system
Spontaneous Reporting System
accessibility
CANADA VAERS
CAERS
MAUDE
TGA
FAERS
JADER Eudra
Lareb KAERS Vigilance Vigibase
AIFA
BfArM
French DB
FEDRA
National SRSs Sovra-national SRSs Worldwide SRSs
Catchment area
History of disproportionality analyses Ed Napke “pigeon holes”, Canada 1968
Disproporzionalità: approcci frequentisti
ADR Sospetta Altre ADR
Farmaco sospetto a b
Altri farmaci c d
PRR ROR
proportional reporting ratio reporting odds ratio
a/(a+b) a*d
PRR = ROR =
c/(c+d) c*b
PRR + 95% IC ROR + 95% IC
Approccio nella ricerca del segnale
Case-by- Case-by-
Statistica Statistica Statistica
case case
soglia
soglia
Case-by-
case
Segnale Segnale Segnale
“DME”
Segnale
Clinical importance
DME: designated medical event (e.g., torsade de pointes, liver injury, severe cutaneous reactions)The need for (and aims of) disproportionality
through spontaneous reporting system
Detection of rare events, especially for newly/recently-
marketed drugs [Curr Drug Saf. 2015;10(3):234-50]
Mapping the overall safety profile [Drug Saf 2010;33:865-78]
Testing/validating a pharmacological hypothesis [Eur Heart J
2005;26:590-7. Diabetes Care 2011;34:1369-71]
Identify drug-drug interactions [Drug Saf 2011;34:253-66]
PV/PD relationship [BJCP 2018;84:2405-2414]
Montastruc et al., Br J Clin Pharmacol 2011;72(6):905-8.
de Boer. Br J Clin Pharmacol. 2011;72(6):909-11.PV/PD relationship
(correlation with receptor affinity)
Int Clin Psychopharmacol. 2019 Mar;34(2):89-92Conceptual and technical challenges in
disproportionality analysis
STUDY CONCEPT
Scientific rationale The scientific basis subtending the study must be clearly described
in the introduction and fall within one of the aforementioned
categories. Timeliness is a requisite
STUDY DESIGN
Choice of The choice of control events is rather problematic and increases
denominator the chance of introducing additional bias (to be considered only
for drugs with established safety profile); choice of control drugs
may have strong impact
Bias identification and The potential existence of various types of bias must be a priori
minimization conceived (depending on the drug and events under investigation)
STUDY RESULTS
Data interpretation Prefer the term “disproportionality signal” or “signal of
disproportionate reporting”, and avoid terms such “association”,
“risk”, “incidence”. Avoid specific clinical recommendations in
terms of risk rankings and identification of safe drugs (inverse
causality does not apply in pharmacovigilance)
Adapted from Raschi et al. NMCD 2018; 28:533-542Limiti segnalazione spontanea (disproporzione)
popolazione che usa il farmaco X
popolazione con ADR
popolazione con ADR segnalata
K1 K2
K1 incidenza di ADR
K2 tasso di segnalazione(MIS)interpretazione ROR: due esempi recenti
Il «caso Elashoff»: un esempio storico che ha fatto discutere
Elashoff AFTERMATH
Riproduzione analisi con il metodo di Elashoff
Metodo Elashoff
Cases Non Cases
Drug (Events) (Controls) OR p Confronto
PANCREATITIS (2004-2009)
Exenatide 518 1114 3,42 5x10-45 * =
Sitagliptin 74 233 2,33 1x10-7 * =
Other Antidiabetics 208 1528
PANCREATITIS (2004-2006)
Exenatide 92 682 1,27 0,12
Sitagliptin 2 18 0,96 1,00
Other Antidiabetics 108 1013
PANCREATIC CANCER (2004-2009)
Exenatide 43 1114 2,68 2x10-4 * =
Sitagliptin 11 233 0,30 3x10-3
Other Antidiabetics 22 1528
THYROID CANCER (2004-2009)
Exenatide 14 1114 3,84 9x10-3 * =
Sitagliptin 1 233 0,76 0,57 =
Other Antidiabetics 5 1528
OTHER CANCER (2004-2009)
Exenatide 267 1114 0,80 8x10-3 *
Sitagliptin 55 233 1,28 0,13
Other Antidiabetics 460 1528ROR cumulative No. of Reports
5 5000
Weber effect Notoriety bias
FDA approval 4500
(April 28, 2005)
4 4000
New indication with TZD
(December 22, 2006)
FDA ALERT UPDATE 3500
ROR cumulative with 95%CI
(August 18, 2008)
No. of Reports
3 3000
FDA ALERT
(October, 2007) 2500
2 2000
1500
1 1000
500
0 0
2005-Q4
2006-Q1
2007-Q4
2008-Q1
2009-Q4
2005-Q2
2005-Q3
2006-Q2
2006-Q3
2006-Q4
2007-Q1
2007-Q2
2007-Q3
2008-Q2
2008-Q3
2008-Q4
2009-Q1
2009-Q2
2009-Q3
Year-QuarterINIBITORI DEL CHECKPOINT IMMUNITARIO: una sfida per clinico, farmacologo e farmacoepidemiologo J Clin Oncol. 2012 Jul 20;30(21):2691-7
Inibitori del checkpoint immunitario: analisi di
disproporzionalità 2018-19
Lancet
Diabetes care
Circulation JAMA Oncology
Lancet Oncology
The OncologistTossicità immuno-relate degli inibitori del checkpoint:
input dalla FarmacoVig per la FarmacoEpi
Hypophysitis/adrenal insufficiency Hepatitis/cholangitis
(anti-CTLA4 drugs) (anti-PD1/PDL1 drugs)
2,266 209 2,061
52
366 310
6,542
Pneumonitis (anti-PD1/PDL1 drugs)
JAMA Oncol. 2018 Dec 1;4(12):1721-1728
Targeted Oncol 2019 accepted for pubblicationLa sfida che ci attende…
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