evolution de la recherche clinique
TRANSCRIPT
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La recherche clinique et l’innovation à l’hôpital en 2019
Enjeux et pratiques
EHESP Rennes
Evolution de la recherche clinique :
les fondamentaux de la recherche clinique
www.ecrin.org [email protected]
Jacques Demotes 20 novembre 2019
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Product centred vs. patient centred research
Registration trials
Repurposing trials
mostly industry
Comparative effectiveness
Personalized medicine
mostly academic
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International cooperation : industry-sponsored vs. academic trials
Atal et al. “Differential Globalization of Industry- and Non-Industry-Sponsored Clinical Trials” PLoS One. 2015 Dec 14;10(12):e0145122.
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International cooperation : industry-sponsored vs. academic trials
Atal et al. “Differential Globalization of Industry- and Non-Industry-Sponsored Clinical Trials” PLoS One. 2015 Dec 14;10(12):e0145122.
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International cooperation clusters : industry-sponsored trials
Atal et al. “Differential Globalization of Industry- and Non-Industry-Sponsored Clinical Trials” PLoS One. 2015 Dec 14;10(12):e0145122.
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International cooperation clusters : academic trials
Atal et al. “Differential Globalization of Industry- and Non-Industry-Sponsored Clinical Trials” PLoS One. 2015 Dec 14;10(12):e0145122.
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Sponsor, investigator, patients
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Clinical research is regulated research : Single sponsor, investigators and patients
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Trial design and methodology
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Levels of scientific evidence
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Interventional
(causality)
Observational
(correlation)
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Overview of clinical development
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Phase I study
Single ascending dose (SAD) healthy (male) volunteers each cohort n=8, 6 active and 2 placebo, blinded, randomised dose escalation (can be stopped at any time) up to MTD (max. tolerated dose, based on number of AEs) PK / PD secondary objective
Multiple ascending dose (MAD) once single dose MTD established cohort n=8, 6 active and 2 placebo, blinded, randomised eg. one dose daily for 10 days evaluate safety and tolerability at steady state
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Single ascending dose
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PK : one-compartment model
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Multiple ascending dose
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Multiple ascending dose
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Phase IIa trials : proof of concept
Relevance AND significance ? -> GO or STOP typically randomized assessment of efficacy statistical significance AND clinical relevance Bayesian methodology suitable clinical relevance / amplitude of effect : define target
clinically relevant difference / placebo (usually lower than effect of reference treatment) and statistical significance vs. placebo (a = 10% 1-sided)
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Phase IIb trials : dose finding
determine dose-response relationship 3 to 4 doses if curve known (Scatchard-like model) 1 – 2 – 4 – 8
what is the effect size ? what is the smallest dose with (almost) maximal effect ? which doses lead to an unacceptable efficacy / safety ?
(therapeutic window ?) choose the dose for the phase III
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Dose finding :
dose-response relationship
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Dose finding :
dose-response relationship
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Overview of clinical development
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Clinical trials : prospective experiment compare randomised groups no confounding factor, causality
Ideally : randomised, double-blind, controlled
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 ?) (ex. ABAAABABAABBAABABAABBB...) blocked (predictability ?) (ex. ABBA ABAB BBAA BAAB....) stratified (balance sex, age)
Clinical trial design and methodology
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Outcome measures standardized, patient-relevant, avoid surrogate endpoints statistical power calculated for primary endpoint
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
Outcome measures and blinding
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Parallel groups patients assigned to one group
Crossover trials
fewer patients, test “within” (not “between”) patients
washout
not if carry-over effect
not for curable diseases or long-term treatments
patients stay for a longer time period in trial
Parallel groups vs. cross-over design
B
A B
B A
A
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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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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
based on n = 2 (Zα + Z [1-β])2 × SD2 /d2 amplitude of effect d (advantage of clinical interest)
estimated variance SD2 (good design reduces variability)
desired power (type-II error, producer’s risk, 1-b = 80-90%)
required significance level (type-I, consumer’s risk, a = 5%)
Statistical considerations in clinical trials
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Trial design and funding decision
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Umbrella and basket trials
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Perpetual trial for a given disease condition
IMI EU-PEARL project
Master protocol
Core outcome sets, endpoints
Common control arm = ‘standard of care’
Single sponsor ? industry ? ‘neutral’ partner ? co-sponsors ?
IP issues ?
Adverse event reporting ?
Multi-arm / multi-drug trials : integrated research platforms
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Secondary use of healthcare or health research data for clinical trials
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reuse of cohort or registry data
reuse of healthcare data :
electronic health records, hospital data warehouses
electronic data capture
reuse of national health databases / insurance data
security, data protection, data standards, interoperability ?
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Commentary: considerations for using the ‘Trials within Cohorts’ design in a clinical trial of an investigational medicinal product. Anna C. Bibby, et al. Trials. 2018;19:18
Schematic representation of the TwiC design
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High-throughput –omics / imaging data ❖ Cohort integration ❖ Multimodal data management ❖ Stratification algorithms ❖ Basket / umbrella trials
Digital revolution in clinical research : Personalised Medicine, PERMIT project
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Regulated research : competent authorities, ethics committees,
insurance, data protection
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European regulatory context for clinical trials
European
Regulations
European Directives
European Member States
National Laws
Competent Authority Rules
Ethical guidelines
Quality System set up by each sponsor
Clinical Trial Regulation 536/2014 Medical Device Regulation 737/2017 General Data Protection Regulation
2016/679
Directives 2001/20/EC (Main) 2005/28/EC (GCP, Monitoring)
2001/83/EC 95/46/CE and 2002/58/EC (Data
protection) 2003/94/CE (Manufacturing and
authorization)
ICH GCP FDA / EMA rules
Quality System
Declaration of Helsinki
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Sponsor
Investigator
Patient
Competent Authority (# FDA)
Ethics Committee
(# IRB)
European legislation on clinical trials: 2001/20/EC
Directive for clinical trials on medicinal products
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EU clinical trial Regulation 536/2014
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Major changes under Clinical Trial Regulation 536/2014
Regulation, NOT a Directive
Risk-based approach of clinical trials
Single application dossier via a EU portal with tacit approval if no response within 60 days
Transparency of clinical trial results
New rules on informed consent of subjects
Introduce the concept of co-sponsorship
Simplified safety reporting system
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2017/745 medical device Regulation Clinical investigation (1)
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Access to market based on closer to FDA approval
Provided by notified bodies, expert groups
Clinical « investigation » required for implantable class III, and active class IIb delivering drugs
Objective : assess safety and performance (efficacy ?)
No guidance on level of evidence, « robustness of data »
Possible scientific advice / expert groups
Single sponsor in the EU (or legal representative)
Provisions for vulnerable populations
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2017/745 medical device Regulation Clinical investigation (2)
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Coordinated clinical trial autorisation / rapporteur country (voluntary until May 2027), opt-out, timelines (45 + 50)
No coordination for ethical review
Compliance with ISO 14155:2011 and with Declaration of Helsinki
Insurance / indemnification (national rules)
Registration, interoperable / EUdraCT, reporting, lay summary
Single electronic portal
Central adverse event reporting system
EUDAMED database, MD identifier (IUD) : transparency, traceability
After label : repurposing -> autorisation, if not -> notification
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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:e018647 http://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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RGPD : de la pseudonymisation à l’anonymisation
Appauvrissement/minimisation
Généralisation, randomisation
N° Nom Prénom DDN Sexe
1 Dupont Gérard 15/09/1987 M
2 Dupond Albert 18/02/1954 M
3 Durant Marcelle 24/02/1968 F
Liste de correspondance (centre)
pseudonymisation
réidentification
Anonymisation
N° Initiales DDN Sexe
Date
d'admission
Date de
chirurgie Motif
1 DG sept-87 M 15/03/2017 18/03/2017 cancer
2 DA févr-54 M 18/04/2017 19/04/2017 hanche
3 DM févr-68 F 19/04/2017 22/04/2017 hanche
Base de données (promoteur)
age à la
chirurgie sexe
Délai
admission
Chirurgie Motif
30 M 3 cancer
63 M 1 hanche
49 F 3 hanche
Données "anonymes"
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Need for multinational cooperation to address global health challenges
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Country National hub
National CTU Network
Czech Republic
Brno CZECRIN
Germany Berlin KKSN Spain Barcelona SCReN
France Toulouse F-CRIN Hungary Pecs HECRIN Ireland Dublin CRCI
Italy Rome ItaCRIN Norway Trondheim NORCRIN Poland Warsaw MRA
Portugal Lisbon PtCRIN Slovakia Kosice SlovaCRIN
Switzerland Berne SCTO
Members
Observers
ECRIN Members / Observers and national partners 350M EU citizens
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ECRIN trial portfolio 57 trials, mean 6.3 countries / trial
participating coordinating
2014 -> 2017
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ECRIN trial portfolio
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ECRIN trial portfolio
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Funding for multinational trials
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International cooperation : industry-sponsored vs. academic trials
Atal et al. “A mapping of 115,000 randomized trials revealed a mismatch between research effort and health needs in none high-income regions J Clin Epi 2018 https://doi.org/10.1016/j.jclinepi.2018.01.006
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CRIGH
Secretariat NIH + ECRIN (OECD and WHO partners)
6 projects
Infrastructure and funding
Global core competencies
Research ethics
Patient involvement
Comparative effectiveness research
Data management and sharing
Clinical Research Initiative for Global Health
www.crigh.org Nature 545:289 (2017)
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Thank you!
Any questions?