Comment adapter la recherche clinique aux différents ... MF/2018/4. Demotes.pdf · new trial...
Transcript of Comment adapter la recherche clinique aux différents ... MF/2018/4. Demotes.pdf · new trial...
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Université Libre de BruxellesActualités en médecine factuelle
Institut Bordet, Bruxelles, 24 février 2018
Comment adapter la recherche clinique aux différents niveaux de preuve ?
Jacques Demotes24 février 2018
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Agenda
Interventional / observational
Evidence along the drug development : efficacy / safety
Pragmatic trials, comparative effectiveness
Personalised / stratified medicine : biomarker profiles, new trial designs
Data reuse, data sharing
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Interventional / observational
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Levels of scientific evidence
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Interventional
(causality)
Observational
(correlation)
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Need for clinical trials
1 - Development of innovative health products
registration trials
phase I – II – III
2 - Repurposing trials
exploring new indications for authorised products
phase II – III
3 - Comparative efficacy/ safety / effectiveness trials
compare efficacy and safety of authorised
healthcare strategies
phase IVNew product
Modified use
registration
phase I II III IV
I>A A>IA>I
I>AI>A
CB
ARisk categories
A>I
Usual care
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Methodology and design
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Methodology and design
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Clinical trials : prospective experiment
compare randomised groups
no confounding factor, causality
Ideally : randomised
double-blind
controlled
Clinical trial design and methodology
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Controls placebo
active comparator
uncontrolled ? placebo effect, regression to the mean
historical control ? patient, treatment, evaluation may differ
ideally concurrent : same time period
Randomisation simple (unbalanced ?)
blocked (predictability ?)
stratified (balance sex, age)
Challenges in randomized clinical trials
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Outcome measures standardized, patient-relevant, avoid surrogate endpoints statistical power calculated for primary endpoint long-term outcome (device) : trial then registry
Blinding : avoid bias double blind : patients and investigators single blind open blinded independent review
Similar treatments, or double-dummy Surgery trials : sham ? Psychotherapy, physiotherapy ? make assessors blind
Challenges in randomized clinical trials
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Learning curve randomise the first patient, analyse 2 groups
Statistical analysis plan pre-specified (and registered) sample size calculation based on primary endpoint
avoid multiple tests and post-hoc analysis
adjustment for multiplicity : Bonferroni, Hochberg
Sample size calculation more patients -> more chance to detect effect (if any)
large effect -> small sample size
n = 2 (Zα + Z [1-β])2 × SD2 /d2
Challenges in randomized clinical trials
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Design : based on question new drug > placebo
new drug + standard > standard
new drug > or = to standard
Superiority, non-inferiority, equivalence
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Insensitive non-inferiority trial
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Evidence along the drug development :
efficacy / safety
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Stages of clinical development
Preclinical Phase I Phase II Phase III Phase IV
Laboratory
Studies
Human Safety Efficacy &
Safety
Post ApprovalComparing
standard
treatment
……………………..…
….
………………………
……………………………….
……………………….…
………..
……………………………………....
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MAA Reimbursement
Non-clinical testingPre-MA• Phase I• Phase II• Phase III
Post-MA• Late phase III - LSS• PASS
(observational / interventional)
• PAES
Evidence along the drug development process
• Late phase III – LST
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Pragmatic trials, comparative effectiveness
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Heterogeneity of patient population
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Personalised / stratified medicine :
biomarker profiles
new trial designs
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Trial centred on the patient, not on the product: what is the best treatment option for this patient / group of patients ?
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Biomarker stratification ?
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Personalised / stratified / precision medicine : biomarker profiling, big data and artificial intelligence
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Clinical data
observational, retrospective or prospective, cohort integration
Omics
Genotype : genomics (germinal, somatic, microbiome)
Phenotype : transcriptomic, proteomic, metabolomic profiles
Imaging
Multimodal data management (secure data warehouse)
Multimodal data analysis for patient stratification
Hypothesis-driven
Data-driven : machine learning
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Non-targeted therapy : tumor histologydetermines treatment
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Ou
Re
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Biomarker-stratified subgroups within the samedisease condition
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Biomarker-stratified subgroups across multiple disease conditions
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Umbrella vs. basket trials
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Umbrella and basket trials beyond cancer ? Treatment options for complex, mechanism-agnostic, biomarker profiles ?
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Data reuse, data sharing
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Reuse of health data for research purposes
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Observational (cohorts) or interventional (trials)
security, data protection, data standards, interoperability
resue of healthcare data :
electronic health records
electronic data capture
reuse of national health databases and registries
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CLINICAL TRIAL DATA SHARING
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development of data sharing plans, tools and services
Ohmann et al., BMJ Open 2017;7:e018647http://bmjopen.bmj.com/cgi/content/full/bmjopen-
2017-018647?ijkey=79SivGTa9igpfbN&keytype=ref
data protection, GDPR informed consent anonymized / pseudonymized access (open vs. controlled) standard data format security type of repositories
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Thank you!
Any questions?