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

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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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Thank you for your kind attention

If you have any questions, please e-mail to

toshi.hamasaki@ncvc.go.jp