randomized evidence on monitoring strategies the optimon study€¦ · to compare two monitoring...
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OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 1 / 26
Valérie JournotINSERM U897 & CIC-EC 7, Bordeaux, France
Randomized evidence on monitoring strategiesthe OPTIMON study
Investigator Pr Geneviève ChêneSponsor Bordeaux University HospitalFunding French Clinical Research Hospital ProgramSupport French university hospitals
INSERMFrench disease-oriented institutions & networksECRIN
https://ssl2.isped.u-bordeaux2.fr/optimon/
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 2 / 26
Back to 2005
European regulationdirective 2001 Clinical Trials
GCP for drug approval trialsin France: any interventional study
GCP widespread interpretation (“gold-standard”)SDV 100% data, 100% patients, 100% sites, on-site monitoring
Protest of (French) academic institutions100% onsite monitoring = 40 to 60% costsefficiency still unprovedhow to optimise cost-efficiency ratio?
cost reduction of on-site monitoring intensity efficiency maintain of fulfilment of regulatory & scientific requirements
the Optimon trial
GCP § 5.18.3 Extent and Nature of Monitoring …The sponsor should determine the appropriate extent and nature of monitoring… In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring… can assure appropriate conduct of the trial in accordance with GCP...
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 3 / 26
Optimon issues
objectiveto compare two monitoring strategies
100% onsite vs. risk-adapted
hypothesisa risk-adapted monitoring strategy can
be defined a priori for each study yield results similar to the 100% onsite strategy for the main quality criteria of studyimprove other aspects, such as costs or delays
a typical non inferiority situation
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 4 / 26
Optimon design
non inferiority trial
ScreeningCTUstudysite
Risk assessmentMonitoring plan
Optimon main eligibility criteriapatient anystudy any clinical field, any design, non risk D level
20 to 100 patients expectedsites 5 patients expectedCTU academic label
experience, GCP compliant
Actions by Optimon team or by study team
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 5 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Stratification = risk levelCluster = site
Actions by Optimon team or by study team
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 6 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Stratification = risk levelCluster = site
Patients’ inclusion and follow-up
Actions by Optimon team or by study team
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 7 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Patients’ inclusion and follow-up
Final cleaningTransfert to Optimon
Actions by Optimon team or by study team
Stratification = risk levelCluster = site
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 8 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Patients’ inclusion and follow-up
Final cleaningTransfert to Optimon
Optimon data
collection
Stratification = risk levelCluster = site
Optimon outcomesprimary
% patient file without error onconsent form signature & SAEs reportmain eligibility criteria & primary outcome
secondaryerrors, delays, costs
Actions by Optimon team or by study team
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 9 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Patients’ inclusion and follow-up
Final cleaningTransfert to Optimon
Statistical analysisby patient
Stratification = risk levelCluster = site
Actions by Optimon team or by study team
Optimon data
collection
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 10 / 26
Optimon design
non inferiority trial
®ScreeningCTUstudysite
risk-adapted
100% onsite
Risk assessmentMonitoring plan
Patients’ inclusion and follow-up
Final cleaningTransfert to Optimon
Statistical analysisby patient
Stratification = risk levelCluster = site
Actions by Optimon team or by study team
Optimon data
collection
Optimon sample size = 5% / 100%onsite = 95% / intrasite = 0,60 1,800 patientsrevised to 900 = 11%
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 11 / 26
Optimon recruitmentCTU 11Risk level 8 A
4 B10 C
Design 16 trial3 cohort3 cross-sectional
Clinical field 6 cancer3 liver & gastr.enter.3 neurology2 nutrition2 rheumatology1 hematology1 infectiology1 intensive care 1 pneumology1 tabacco1 urology
Population 14 adults4 children2 women2 elderlies
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 12 / 26
1. to assess study characteristicswithout any glance at the resulting risk level
Pre Optimon risk assessment scaleContemp Clin Trials 2011;32(1):16-24
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 13 / 26
1. to assess study characteristicswithout any glance at the resulting risk level
Pre Optimon risk assessment scale
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 14 / 26
1. to assess study characteristicswithout any glance at the resulting risk level
Pre Optimon risk assessment scale
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 15 / 26
2. to deduce the risk level
Pre Optimon risk assessment scale
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 16 / 26
2. to deduce the risk level
Pre Optimon risk assessment scale
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 17 / 26
2. to deduce the risk level
Pre Optimon risk assessment scale
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 18 / 26
100% onsite monitoring risk-adapted monitoringrisk level
Arisk level
Brisk level
C
set-up
initial contact systematically and tracedsite adequation systematically, remotely if site known and experimented
otherwise on site (may be coupled with set-up)initiation systematically, before inclusion of 1st patient, by phone if site known and experimented,
otherwise on site
data monitoring
on-site monitoringdata conformity
respect of procedures
on site, 100% patients,100% data, 100% sites
(freq. to be defined at study start)
10% patients100% key points
then if major problem
1 visit / site100% key points
then is major problemcomprehension of
circuits systematically, on site, at 1st
monitoring visit (from 1st inclusion)systematically, by phone
after reception of forms of 1st patient at CTU/CRCconsents systematically, on site
at next visitmasked copy at inclusion
on site at next visit or at closuresearch for SAEs systematically, on site systematically, on site or remotely
corrections at each visit, 100% dataqueries created remotely or on site
at each visit for key pointsqueries created remotely
forms verification systematically, before entry of forms not checked on site
centralized monitoring systematically, 100% patients, 100% data, 100% sites + respect of procedures
close-outsystematically, on site
100% patients, 100% sitessystematically, par mail
100% patients, 100% sitessystematically, on site
100% patients, 100% sites
Pre Optimon risk-adapted monitoring plan
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 19 / 26
on-site monitoring
key points key data, respect of procedureskey data patient's existence, consent form signature, primary outcome,
main eligibility criteria, main exams and visits, main secondary outcomes
Pre Optimon risk-adapted monitoring plan
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 20 / 26
on-site monitoring
key points key data, respect of procedureskey data patient's existence, consent form signature, primary outcome,
main eligibility criteria, main exams and visits, main secondary outcomes
centralized monitoring
Pre Optimon risk-adapted monitoring plan
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 21 / 26
Rationalehigh inter-assessor variability observed in Pre Optimonneed for risk assessment independent from sponsor validation committee
2 clinicians, 2 methodologists, 2 sponsor representativesindependent assessmentconsensus search if needed
Summary of results24 studies assessedinitial consensus reached for 2/3 studiessponsors tend to a higher risk level
collective risk assessmentby trained assessors
Risk assessment in Optimon
methodologists clinicians sponsors
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 22 / 26
original
Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 23 / 26
TO BE CHECKED
Investigator-signature-name-date of signature-contact info.
Participant-anonymization-name-date of signature-signature
Trial-identification
Consent form-version
original
Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 24 / 26
TO BE CHECKED
Investigator-signature-name-date of signature-contact info.
Participant-anonymization-name-date of signature-signature
Trial-identification
Consent form-version
original masked copy
something visible, not legible
Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 25 / 26
Limitsguesstimated sample size and powerrisk for participant only / one-for-all strategy
outdated
Strengthsrandomized clinical trial
high level of evidenceonly 2 such trials: Optimon and Adamon
risk for participant only= minimal level of monitoring
one-for-all strategy proof of concept
movement for development of the approachECRIN, OECD, FDA, EMA, EC (drug) trialsOptimon any study design or phase
Optimon in the regulation changing context
OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 26 / 26
Valérie JournotINSERM U897 & CIC-EC 7, Bordeaux, France
Randomized evidence on monitoring strategiesthe OPTIMON study
Investigator Pr Geneviève ChêneSponsor Bordeaux University HospitalFunding French Clinical Research Hospital ProgramSupport French university hospitals
INSERMFrench disease-oriented institutions & networksECRIN
https://ssl2.isped.u-bordeaux2.fr/optimon/