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Improving the Quality of Clinical Trials in Network for Clinical Stroke Trials
Toshimitsu Hamasaki, PhD, Pstat® National Cerebral and Cardiovascular Center
“New Trends in Clinical Trials”, Taipei, Taiwan. November 23, 2016
Six National Disease Centers in Japan
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National Cerebraland CardiovascularCenter National Cancer Center
National Center of Neurology and Psychiatry
National Center for Global Health and Medicine
National Center for Children Health and Development
National Center for Geriatrics and Gerontology
National Cerebral and Cardiovascular Center (NCVC)
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Vein(静脈)
Artery(動脈)
CerebralIntelligence
Cardiovascular Passion
National Cerebral and Cardiovascular Center: Outline
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No. of patient’s beds General wards: 468/Special wards: 172
No. of outpatients per day: 640Main Clinical Specialties Cardiology Coronary disease Arrhythmia Heart failure Cardiac transplantation Congenital heart disease Pulmonology circulation Stroke Kidney disease other diseases
Two Major Functions for Clinical Trials Conducts at NCVC
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Dept. of Data ScienceDirector (1)Dept. Secretory (1)
Biostat and Data ManagementBiostat (3) + DM (3)
Trial Quality MonitoringTrial Monitor (3)
Project ManagementProject Manager (1)
Center for Advancing Clinical andTranslational Sciences (ACTS)Director (1)/Associate Director (1)
Clinical Research Coordination Clinical Research Coordinator(10)
Trail ManagementTrials Manager(3)
Public Awareness & Consultation Consultant (3)
Our Department Mission
To be a team of highly skilled and experienced project coordinators, database developers, data managers, biostatisticians, regulatory staff and administrators committed to providing high quality infrastructure and support for multicenter clinical trials
To be a successful supporting groups of academic researchers needing infrastructure support.
To be eager to collaborate with individuals and groups committed to high quality research that require expert statistical design and analysis, database development, data management, and protocol coordination support
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Our Major Supports for Better Clinical Trials
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Planning Conducting Closing
Study Design and Protocol Development
Integrated trial management systemsRegistration & randomization EDC and Data collectionData management Participant trackingCentralized trial monitoring AE Reporting
Manual creation (manuals of operation, manuals of procedures)
System User training Technology assessmentsWebsite development and
management Project management Statistical analysis plan
development
Interim analysis DSMB support/report Data trackingReal-time data element/visit
trackingParticipant tracking and
scheduling systemsAutomated e-mail messages
– including reminders and randomization
Data clearing and coding Trial monitoringScreening and enrollment
reportsCustom reports for study
coordinatorsData quality and missing data
reportsFollow-up rate reportsOnsite-monitoring
Blinded review Database lock/release Database storage Analysis data set creation Data analysis and complex
statistical programming Abstract analysis and
collaboration Manuscript analysis and
collaboration Additional expertise- Statistical
consulting
Data Management Process and Corresponding SOPs at NCVC
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Trial planning and initiation Trial conduct Trial closing
Dat
a M
anag
emen
t Pro
cess eCRF design
Meta data design Data management
software/system selection and design
Database validation plan preparation
Database/system validation Data management plan
preparation End-user training
Data collection Data entry Data clearing Data coding Data tracking Centralized trial
monitoring
Dataset lock and release Dataset storage Data management report
SOPs
Contracting (103)Data Management process
and plan (201) Data management software
system selection (202)eCRF designs (203)Security management (204)End-user training (205)
Data collection and entry (207)
Data clearing (208)Data coding (209)Data tracking (210)Centralized trial monitoring
(211)
Dataset lock and unlock (212)
Dataset storage and documentations (213)
# of Newly Supported Trials
9
0
2
4
6
8
10
2012 2013 2014 2015 2016
# of
tria
ls
NDA trialsType B trialsOther trialsOthers
NDA trials: Clinical Trials for New Drug/Device Application Type B trials: Clinical Trials for unapproved or off-label drugs/devices under “Advanced Medical Service System”Other trials: “non-NDA” or “non Type-B” clinical trials Others: Observational studies
# of on-going trials: 25 trials
Recent Major Changes in Trial Conduct in Japan
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NDA Clinical Trials“Chiken”
Non-NDA Clinical Trials(Interventional
Trials)
Observational and Epidemiological Studies
Regulation and Guidance ICH-GCP
Local restriction (Japanese-GCP)
Ethical Guidelines for Medical and Health Research Involving Human Subjects
MonitoringMandatory Not required (until
2014)if necessary Not required
Audit Mandatory Not required (by
2014)if necessary Not required
http://www.lifescience.mext.go.jp/files/pdf/n1500_01.pdf
FullyRevised, Ethical Guidelines for Medical and Health Research
Part 20 Monitoring and Audit(1) The principal investigator shall endeavor to secure the reliability of research and
when carrying out research which involves invasiveness (not including minor invasiveness) and intervention, shall perform monitoring and, as necessary, audit, in accordance with the specifications prescribed in the research protocol approved by the chief executive of the research implementing entity..
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http://www.lifescience.mext.go.jp/files/pdf/n1500_01.pdf
Network for Clinical Stroke Trials in Japan: NeCST
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Toyoda K et al (2016) Stroke 47:304-305.
NeCST: Major Challenges
is designed to maximize efficiencies to prioritize, harmonize and streamline the development of high-quality, multi-site clinical trials focused on key interventions in stroke prevention, treatment, and recovery.
provides centralized infrastructure and support for data management and integration as well as opportunities for data sharing
establishes strong multidisciplinary collaboration within and among networking-sites to ensure successful completion of trials .
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Funding Centralized infrastructure
Collaborations Ongoing Trials
NeCST: Structure
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Data coordinating center
Imaging center
Centralized trial monitoring in NeCST
Centralized trial monitoring: an approach to better quality and integrity in clinical trials Helps in early identification and mitigation of data quality risk/issue(s) which
may compromise validity of study results Supports in better monitoring of patient safety and helps in enhancing
subject protection Keeps track of sites’ performances to help plan on-site monitoring visitsOptimizes on-site monitoring visits Creates overall efficiencies in clinical trial operationsOn-going centralized trial monitoring THAWS trial: THrombolysis for Acute Wake-up and Unclear-onset Strokes
With Alteplase at 0.6 mg/kg Triall
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Centralized and On-Site Trial Monitoring Decision
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Risk of Intervention ⋯ High or Low Size of a trial ⋯ Small or Large # of sites ⋯ Single or Multi
On-site monitoring and SDV
Centralized trial monitoring
Identify risks
THAWS trial
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Koga M et al. (2014) International Journal of Stroke 9:1117–1124.
THWA Trial: Trial Design
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A multicenter, randomized, open-treatment, blinded-end-point trial to determine the efficacy and safety of intravenous thrombolysis with alteplase at 0·6 mg/kg body weight, in ischemic stroke patients with unclear time of symptom onset, and compare findings with standard treatment.
The design is similar to WAKE-UP Stroke trial, and pre-planned to established the similarity of the result
300 patients/40sites
A multicenter investigator-initiated randomized placebo-controlled clinical trial of MRI based thrombolysis in acute stroke patients with unknown time of symptom onset, e.g. due to recognition of stroke symptoms on awakening.
Risk minimization
Periodical Risk
monitoring and
reporting
Reporting process for distributing communications and framework for decision-making
Monitoring reporting format and frequency(once a month)
Major risk indicators and their thresholds Participant eligibility and protocol
deviation/violation Adverse events /serious adverse
events (Frequency and severity) Time to data entry and # missing
data # of issued DCF and data-entry
errors/corrections
THAWS Trial: Centralized Trial Monitoring
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Issue DCF Share common errors with trial
investigators Evaluate the need of on-site
monitoring for any specific center
Centralized Monitoring Plan Assessment by team including central monitors, medical reviewers, data managers, and biostatisticians
Risk assessment
THAWS Trial: Issues Identified by Centralized Trial Monitoring
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Participant eligibility & protocoldeviation/violation Patients safety (AE/SAE) OthersInclusion/Exclusion criteria mRS score (3) PLT count (4) Treatment starting
time (5) JCS score (1) NIHSS score (1)
AE double entry (2)
16 DCF issues and 15 resolved as of May 24. 2016
Identified 5 of 35 sites as ones with some risks
Conducted one-site monitoring for these five sites and asked the responsible person to produce the plan for improvement
THAWS Trial: Creating and Evaluating the Reports
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Extracting data from Web-based EDC(REDCap)
Creating the reports by In-
house validated SAS
codes
Evaluate the reports via documents
management system
“Independent” Systems for Supporting Clinical Trials
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Integrated sytem solution
EDC RedCAP™
Satellite
Inefficient an ineffective working process redundant data entry in multiple
systems. data discrepancies between
systems. inefficient trial operation
management. larger burdens for sites and
coordinating centers. Customer/stakeholder
unfriendly Difficulty in maintenance for
systems/software
e-mail based
randomization
Centralizedmonitoringreporting
Toward the Next Stage
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EDC & Data Processing
Participants Registration & Randomization
Centralized Monitoring & Remoted SDV
Safety Monitoring& Reporting
Statistical Analysis& Reporting
Data Sharing
Data ProtectionSecurity, Backup& Recovery
RegulatoryCompliance
Integrated Solution
Provides web-based solution for centralizing the management aspect of clinical trials
Enables informed decision-making based on real-time data gathering and monitoring
Provides simplified and streamlined clinical process with reduced resources
A New SaaS-based Clinical Trial Management System at NCVC
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Secured Service by Fujitsu
Central Data CenterFujitsu Shikoku Data Center
Network
StorageSoftware
DDWork21/EDC plusTsCollaborationCustomized for NCVC
Database design
Data entryData clearingData codingData tracking
eCRFdesign
ScreeningRegistrationRandomization
Remote SDVCentralized trial
monitoring
SAE reporting
Statistical analysis &
reporting
Documentations
SaaS: Software as a service
Feature Checklist
Electronic data capture
Subject database
Registration and randomization
Centralized trial monitoring
Document management
SAE reporting & management
Regulatory complianceFDA 21 CFR Part 11MHLW Guidance on electronic signature FDA Guidance for industry Electronic Source Data In Clinical Investigations
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Data sharing /standardization toolsMedDRA/WHO-DD codingCDISC-compliant system
Multilingual language supports
Statistical analysis & reporting (not yet customized)
Low cost (USD2000 per protocol/per month, not depending on the number of participants/amount of data)
Summary
One of our major issues in academic-research initiated clinical trials is how to improve quality and integrity of clinical trials with limited human recourses and budget
Centralized trial monitoring is one of approaches to better quality and integrity in clinical trials. It helps in early identification and mitigation of data quality risk/issue(s), supports in better monitoring of patient safety and helps in enhancing subject protection, keeps track of sites’ performances to help plan on-site monitoring visits, optimizes on-site monitoring visits, creates overall efficiencies in clinical trial operations
But “cost-efficient” centralized trial monitoring requires integrated system solution: integrated system solution can eliminates redundant data entry in multiple systems, prevents data discrepancies between systems. enhances trial operation management efficiency, and reduces burdens for sites and coordinating centers.
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