from natalizumab and edmus - europa
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Christian CONFAVREUXChristian CONFAVREUX
Hospices Civils de LyonHospices Civils de LyonUniversitUniversitéé
Claude Bernard Lyon 1Claude Bernard Lyon 1Fondation EugFondation Eugèène ne DevicDevic
EDMUSEDMUS
London, EMA, July 25London, EMA, July 25--26, 201126, 2011
FromFrom
NATALIZUMAB and EDMUSNATALIZUMAB and EDMUS
to TYSEDMUSto TYSEDMUS
and OFSEPand OFSEPTysabriTysabri®®
in French EDMUS Databasesin French EDMUS Databases
Observatoire FranObservatoire Franççais de la Sclais de la Scléérose En Plaquesrose En Plaques
EuropeanEuropean
DatabaseDatabase
for Multiple for Multiple SclerosisSclerosis
Natalizumab
(Tysabri®)
Marketing Approval
in France
Agence Française de Sécurité
SAnitaire
des Produits de Santé(AFSSAPS) & Risk
Management Plan
20072007
Polman et al. NEJM 2006; 354: 899Polman et al. NEJM 2006; 354: 899--910910
EFFICACYEFFICACY
as as comparedcompared
to placebo, to placebo, atat
2 2 yearsyearsAccumulation of Accumulation of DisabilityDisability
42 % 42 % Relapse Rate Relapse Rate 68 % 68 % MRI MRI ActivityActivity
92 % 92 %
TOLERANCETOLERANCE
SAFETYSAFETY
20062006
The Care of MS in France (1)
63 63 CentresCentres
28 28 UniversityUniversity
HospitalHospital
ReferralReferral
MS CentresMS Centres
18 18 City and City and HospitalHospital
HealthHealth
RegionalRegional
NetworksNetworks
The EDMUS NetworkThe EDMUS Network
The EDMUS SoftwareThe EDMUS Software
The Care of MS in France (2)
●● BIOMEDBIOMED
●● BIOMEDBIOMED1st 1st EuropeanEuropean
22ndnd EuropeanEuropeanConcertedConcerted
ConcertedConcertedActionAction
ActionAction
19571957
19761976
19801980
19901990
19921992
19931993
●● OnsetOnset
●● NaturalNatural
●● NaturalNatural
●● EDMUSEDMUSLyonLyon
HistoryHistory
HistoryHistory
JNNPJNNPMS MS CohortCohort
ThesisThesis
BrainBrain
●● EDMUS Software V1EDMUS Software V1
●● EDMUSEDMUSFoundationFoundation
●● MultiMulti--
●● ARS RhôneARS Rhône--AlpesAlpes
●● PHRCPHRCSponsorshipSponsorship
RRééseau RASEPseau RASEP
NOMADMUSNOMADMUS
●● OFSEPOFSEPPharmaceutical Pharmaceutical ●● PHRC PHRC ●● PHRC PHRC ●● AFSSAPS AFSSAPS ●● BiogenBiogen IdecIdec
InvestissementsInvestissementsIndustryIndustry
IRMUSIRMUS
POPARTMUSPOPARTMUS
TYSEDMUSTYSEDMUS
TYSEDMUSTYSEDMUS
dd’’Avenir ANRAvenir ANR
19981998
20002000
20012001
20042004
20052005
20072007
20102010
20112011
●● PRIMSPRIMS
●● NaturalNatural
●● VACCIMUSVACCIMUS
●● KIDMUSKIDMUSNEJMNEJM
HistoryHistory
NEJMNEJM
NEJMNEJMNEJMNEJM
Mai 2011Mai 2011
285 Centres285 Centres40 Countries40 Countries
DiffusionDiffusionof EDMUSof EDMUSWorldwideWorldwide
Use of EDMUS in France
Electronic
Medical
Record
Fully
Integrated
in Daily Medical
Practice
Directly
Indirectly
"Subcontracted"
A A CohortCohort
The Care of MS in France (3)
>32.000 >32.000 PwMSPwMS
Pregnancy
Natural HistoryVaccinationsChildhood
Onset
TYSEDMUS
Observational prospective phase IV Observational prospective phase IV pharmacopharmaco--epidemiological followepidemiological follow--up study up study of patients with MS and treated with of patients with MS and treated with natalizumabnatalizumab
in France in France based on the French network of neurologists using EDMUSbased on the French network of neurologists using EDMUS
SponsorSponsor
AFSSAPSAFSSAPS
SupportsSupports
FondationFondation
EugEugèènene
DevicDevic
EDMUSEDMUSHospices Hospices CivilsCivils
de Lyonde LyonSociSociééttéé
FranFranççaiseaise
de de NeurologieNeurologie
(SFN)(SFN)FFééddéérationration
FranFranççaiseaise
de de NeurologieNeurologie
(FFN)(FFN)BiogenBiogen
Idec France (Unconditional Grant)Idec France (Unconditional Grant)
Coordination Coordination LYON EDMUS LYON EDMUS CoordinatingCoordinating
CentreCentrewww.edmus.org www.edmus.org [email protected]@edmus.org
ScientificScientific
CommitteeCommitteePr. Christian CONFAVREUXPr. Christian CONFAVREUX
Pr. Michel CLANETPr. Michel CLANETDr. Anne CASTOT (AFSSAPS)Dr. Anne CASTOT (AFSSAPS)
Dr. Fanny ROCHER (CRPV)Dr. Fanny ROCHER (CRPV)Dr. Eric VAN GANSEDr. Eric VAN GANSEPr. Sandra VUKUSICPr. Sandra VUKUSIC
CoordinatingCoordinating
CentreCentreNadine PASSANTE (CRA)Nadine PASSANTE (CRA)Julie BORGETTO (CRA)Julie BORGETTO (CRA)
Marion DUFOUR (Statistician)Marion DUFOUR (Statistician)Bernard FRANGOULIS (EngineerBernard FRANGOULIS (Engineer)
InvestigatorsInvestigators
Dr AL KHEDR Dr AL KHEDR AbdullatifAbdullatif, Dr ANDRODIAS G, Dr ANDRODIAS Gééraldine, Dr ANNE Olivier, raldine, Dr ANNE Olivier, Dr AUFAUVRE Dominique, Dr BERGER Eric, Dr BERROIR StDr AUFAUVRE Dominique, Dr BERGER Eric, Dr BERROIR Stééphane, phane,
Dr BESSON GDr BESSON Géérard, Dr BOUILLAGUET Sophie, rard, Dr BOUILLAGUET Sophie, Pr BRASSAT David, Pr BROCHET Bruno, Dr CABRE Philippe, Pr BRASSAT David, Pr BROCHET Bruno, Dr CABRE Philippe,
Dr CAMDESSANCHE JeanDr CAMDESSANCHE Jean--Philippe, Pr CAMU William, Dr CASEZ Philippe, Pr CAMU William, Dr CASEZ Olivier, Dr CASTELNOVO Giovanni, Pr CLANET Michel, Olivier, Dr CASTELNOVO Giovanni, Pr CLANET Michel,
Pr CLAVELOU Pierre, Dr CLERC Christine, Pr CONFAVREUX Christian,Pr CLAVELOU Pierre, Dr CLERC Christine, Pr CONFAVREUX Christian,
Pr CREANGE Alain, Dr CREISSON Eric, Dr DE MARCO Olivier, Pr CREANGE Alain, Dr CREISSON Eric, Dr DE MARCO Olivier, Pr DE SEZE JPr DE SEZE Jéérôme, Pr DEBOUVERIE Marc, Pr DEFER Gilles, rôme, Pr DEBOUVERIE Marc, Pr DEFER Gilles,
Dr DOUBRERE JeanDr DOUBRERE Jean--FranFranççois, Dr DURANDois, Dr DURAND--DUBIEF FranDUBIEF Franççoise, oise, Pr EDAN Gilles, Dr EVRARD Serge, Pr GODEFROY Olivier, Pr EDAN Gilles, Dr EVRARD Serge, Pr GODEFROY Olivier,
Dr GRIMAUD JDr GRIMAUD Jéérôme, Dr GUENNOC Annerôme, Dr GUENNOC Anne--Marie, Dr HABAMarie, Dr HABA--RUBIO RUBIO JosJoséé, Pr HANNEQUIN Didier, Pr HAUTECOEUR Patrick, Dr HEINZLEF , Pr HANNEQUIN Didier, Pr HAUTECOEUR Patrick, Dr HEINZLEF
Olivier, Pr LABAUGE Pierre, Dr LAPLAUD DavidOlivier, Pr LABAUGE Pierre, Dr LAPLAUD David--Axel, Dr LEBRUNAxel, Dr LEBRUN--
FRENAY Christine, Mme LEFRERE Fabienne, Pr LUBETZKI Catherine, FRENAY Christine, Mme LEFRERE Fabienne, Pr LUBETZKI Catherine, Pr MAGY Laurent, Dr MARIGNIER Romain, Pr MOREAU Thibault, Pr MAGY Laurent, Dr MARIGNIER Romain, Pr MOREAU Thibault,
Pr NEAU JeanPr NEAU Jean--Philippe, Dr OUALLET JeanPhilippe, Dr OUALLET Jean--Christophe, Dr OUBARY Christophe, Dr OUBARY Paul, Dr PAPEIX Caroline, Pr PELLETIER Jean, Dr RICO Audrey, Paul, Dr PAPEIX Caroline, Pr PELLETIER Jean, Dr RICO Audrey, Dr RUGGIERI IrDr RUGGIERI Irèène, Pr RUMBACH Lucien, Dr SLESARI ne, Pr RUMBACH Lucien, Dr SLESARI IulianaIuliana, ,
Dr STANKOFF Bruno, Dr FrDr STANKOFF Bruno, Dr Frééddééric TAITHE, Dr Eric THOUVENOT, ric TAITHE, Dr Eric THOUVENOT, Pr TOURBAH Pr TOURBAH AymanAyman, Dr VENTRE Jean, Dr VENTRE Jean--Jacques, Pr VERMERSCH Jacques, Pr VERMERSCH Patrick, Dr VIALLET FranPatrick, Dr VIALLET Franççois, Pr VIGHETTO Alain, Pr VUKUSIC ois, Pr VIGHETTO Alain, Pr VUKUSIC
Sandra, Dr WIERTLEWSKI Sandrine, Dr ZIEGLER FranSandra, Dr WIERTLEWSKI Sandrine, Dr ZIEGLER Franççois, ois, and all the and all the neurologistsneurologists
involvedinvolved
in the in the regionalregional
citycity--hospitalhospital
MS MS networks.networks.
ParticipantsParticipants
PrimaryPrimary
Establish the
Safety ProfileSafety Profile
of NTZ (short to long term) in real life settingsDetermine the
Incidence of Adverse EventsIncidence of Adverse Events, notably, notablyinfusion-related events, hypersensitivity reactions, development of anti-NTZ antibodies,infections: serious, opportunistic,pregnancies and pregnancy outcomes, malignancies
ObjectivesObjectives
SecondarySecondary
Describe the
Evolution
of patients treated with NTZ (relapses, EDSS, MRI)Determine the
Conditions of UseConditions of Use
of NTZ in real life settingsCompare the incidence of serious and/or opportunistic infections
and malignancies, between a
Non-Exposed Population
and the NTZ-exposed one
InclusionsInclusions
395039203800
3500
32503100
2900
25502350
2100
1700
1325
970
575
187
2141
229131
16771575
1071
284
14001481
1420
1859
23082251
2180
12961163
1012
751531
471
28552855
881610
28602800
17001670
363
3351
1376
36983698
3351
930
1767
3134
743
0
500
1000
1500
2000
2500
3000
3500
4000
Apr-07 Oct-07 May-08 Nov-08 Jun-09 Dec-09 Jul-10 Jan-11
Cumulat
ive
no o
f pa
tien
ts
No of treated
patients (France)
Effective inclusions
Promised
inclusions (Incl. Effective)
±± 40004000
BiogenBiogen
CharacteristicsCharacteristics
atat
InclusionInclusion
Age (mean
± SD)
37.7 ± 9.8 yrFemale : Male Ratio
3 : 1
Disease Duration (mean
± SD)
9.1 ± 6.7 yrDisease Course (% patients with RRMS)
96 %Prior Disease-Modifying Treatments (% patients)
Immunomodulators
88 % Immunosuppressants
22 %None
10 %
Nb Relapses in the Previous
12 Months
(mean
± SD)
1.9 ± 1,2EDSS score (mean
± SD)
3.6 ± 1,8Brain MRI with Gad+ Lesions
55 %
425 (16%) patients definitively stopped 425 (16%) patients definitively stopped natalizumabnatalizumab487 treatment discontinuations487 treatment discontinuations
••
32 % = Adverse Events, Allergy, Persisting Neutralizing Antibodi32 % = Adverse Events, Allergy, Persisting Neutralizing Antibodies, es, ……••
23 % = Lack of Efficacy (Relapses, Secondary progression)23 % = Lack of Efficacy (Relapses, Secondary progression)••
45 % = Pregnancy, Convenience, 45 % = Pregnancy, Convenience, ……
Follow-up
Duration Duration MMeanean
±± SDSD
20.1 20.1 ±± 13.9 months13.9 monthsMedian [Range]Median [Range]
19.5 [0 19.5 [0 ––
57] months57] months
SeveritySeverity DescriptionDescription InfusionInfusionNoNo
NTZ NTZ StoppedStopped
DeathDeath
PMLPML 1818 --Acute Acute LeukoencephalopathyLeukoencephalopathy
((mycoplasmamycoplasma)) 1919 --CardiacCardiac
arrestarrest 1414 --CardiacCardiac
arrestarrest 22 --CompletedCompleted
suicide by suicide by defenestrationdefenestration 1414 --CompletedCompleted
suicide by suicide by drugdrug
overdoseoverdose 1818 --
Persistent or Persistent or significantsignificant
disabilitydisability CarotidCarotid
ArteryArtery
Dissection, Dissection, SylvianSylvian
InfarctionInfarction 2121 NONO
LifeLife--threateningthreatening
PMLPML 3232 YESYESEncephalitisEncephalitis
due to herpes simplexdue to herpes simplex 2323 YESYESUrticariaUrticaria, , extendedextended 22 YESYES
Suicide Suicide attemptattempt
by by drugdrug
overdose & overdose & cuttingcutting
femoralfemoral
veinvein 1717 UnknownUnknown
Suicide Suicide attemptattempt
by by drugdrug
overdoseoverdose 1818 NONO
Suicide Suicide attemptattempt 1111 NONO
CardioCardio--respiratoryrespiratory
arrestarrest
due to due to drowningdrowning 1010 NONO
Safety
164 Serious Adverse Events among 128 patients (4.5%)164 Serious Adverse Events among 128 patients (4.5%)
SeveritySeverity
DescriptionDescription
InfusionInfusion
NTZNTZNoNo
StoppedStopped
PMLPML
1919
YESYESPMLPML
3939
YESYESPMLPML
3434
YESYESPMLPML
UnknownUnknown
YESYESPMLPML
UnknownUnknown
YESYESPMLPML
UnknownUnknown
YESYES
BB--cellcell
lymphomalymphoma,,
3333
YESYESSmall Small cellcell
lunglung
cancercancer
2727
YESYESRectum cancerRectum cancer
77
YESYESHospitalisationHospitalisation
BreastBreast
CancerCancer
UnknownUnknown
YESYESBreastBreast
cancercancer
4343
NONOUterusUterus
cancercancer
2626
NONOSkin cancer Skin cancer 3030
NONO
AnaphylacticAnaphylactic
shockshock
22
YESYES14 14 AllergicAllergic
reactionsreactions
22x9,x9,
33x2x2,,
55x2,x2,
66x1x1
YESYES
Acute Acute retinalretinal
necrosisnecrosis
due to VZVdue to VZV
2121
YESYESMeningitisMeningitis
due to due to EnterovirusEnterovirus
11
YESYESHerpes Herpes ZosterZoster
shinglesshingles
33
NONOTuberculosisTuberculosis
((MycobacteriumMycobacterium
aviumavium))
2929
UnknownUnknown
CytolyticCytolytic
hepatitishepatitis
3434
YESYES
Efficacy
AtAt
StartingStarting
YearYear
11
YearYear
22
YearYear
33NTZNTZ
NTZNTZ
NTZNTZ
NTZNTZ
RelapsesRelapses((MeanMean
AnnualizedAnnualized
Relapse Rate)Relapse Rate)
EDSS Score EDSS Score ((MeanMean
±± SD)SD)
3.7 3.7 ±± 1.81.8
3.3 3.3 ±± 1.91.9
3.4 3.4 ±± 1.91.9
3.5 3.5 ±± 2.02.0
The Observatoire FranThe Observatoire Franççais de la SEPais de la SEP(OFSEP)(OFSEP)
10.341.968 10.341.968 €€
over 10 over 10 yearsyears
A A ""LargeLargeEpidemiologicEpidemiologic
ToolTool""
FOR WHOM ? FOR WHOM ? PhysiciansPhysicians, , ResearchersResearchers,,
HealthHealth
AuthoritiesAuthorities,,IndustryIndustry
WHERE ?WHERE ?France and ROWFrance and ROW
FOR WHAT ?FOR WHAT ?PromotePromote
ResearchResearch
…………
ClinicalClinical,,TranslationalTranslational,,
BasicBasic
TheTheNationalNational
MS MS CohortCohort
IncreaseIncreaseEnrichEnrich
DiversifyDiversify
SupplementarySupplementary
NestsNestsInaugural EpisodesInaugural Episodes
CancersCancersGeneticGenetic
EpidemiologyEpidemiology
PharmacoPharmaco--EpidemiologyEpidemiologySafetySafety, , ToleranceTolerance, ,
Conditions of PrescriptionConditions of PrescriptionAFSSAPSAFSSAPS
PharmacoPharmaco--EconomyEconomyCostCost
/ / EfficacyEfficacyCNAMTS, RSI, MSACNAMTS, RSI, MSA
PharmacologyPharmacologyEfficacyEfficacyHAS, CTHAS, CT
Perma
nent M
ulti-D
rug Ph
armaco
-Epid
emiolo
gical
Survei
llance
Syste
m
for M
ultiple
Scler
osis in
France
Perma
nent M
ulti
Perma
nent M
ulti--D
rug Ph
armaco
Drug P
harma
co--Epi
demiolo
gical
Epidem
iologic
al Surv
eillanc
e Syst
em
Survei
llance
Syste
m
for M
ultiple
for M
ultiple
Scler
osis
Sclero
sisin
France
in Fra
nce