presents

Implementing a clinical data management randomization system aimed to satisfy research regulationsMichael Duvenhage, Operations Manager

National Institute of Allergy and Infectious Diseases, NIH

Clinical Data Management Support Operational Support Overview

Cambodia = 5

Thailand = 1

Cameroon = 2

China = 2India = 3

Mali = 31

Tanzania = 2

Uganda = 26South Africa = 3

Ghana = 1

Korea = 2Burkina Faso = 1

USA = 3

Senegal = 1

Overview• Countries: 15• Active DataFax Studies: 81• DataFax Studies in Setup: 5• Archived Studies: 11 (previous server)• Studies Terminated without Stating: 2• Total CRF pages: 1,856,625• Active Users: 204

Bangladesh = 1

256473

122700

148262128458

0

50000

100000

150000

200000

250000

300000

2015 - Q4 2016 - Q1 2016 - Q2 2016 - Q3

CRF Page submissions into DataFax(2015 Q4 – 2016 Q3)

ALASKA (USA)

CANADA

UNITED STATES AMERICA

MEXICO

GREENLAND(DENMARK)

ICELAND

FARCA ISLANDS UNITEDKINGDOM

FRANCE

VENEZUELA CENTRAL

AFRICAN

REPUBLIC

DEMOCRATIC

REPUBLIC

OF CONGO

ALGERIA

NIGERMALICHAD

SUDANERITREA

TUNISIA

MAURITANIA

WESTERN

SAHARA

SENEGAL

GUINEA

LIBERIA

NAMIBIA

ZIMBABWE

ANGOLAZAMBIA

BOTSWANA

SOUTHAFRICA

KENYA

TANZANIA

CONOGO

CABON

CAMEROON

NIGERIA

BURKINAFASO

COLOMBOA

GUYANA

SURINAMEFRENCHGUIANA

ECUADOR

PERU

BOLIVIA

BRAZIL

PARAGUAY

ARGENTINACHILEURUGUAY

BELIZEA

HONDURAS

NICARAGUA

GUATEMALA

SALVADORCOSTA RLCA

PANAMA

HAITI DOM.CUBU

BAHAMAS

G.B.

SIERRA L. LVORY

COAST

TOGO

BENION

LES.

SWA.

MADAGASCAR

MALAWI

BU.

SWI.

GARMANYBEL.

NORWAY

DENMARK

ETHIOPIA

JAM.

MOZAMBIQUE

SOMALIA

LIBYA EGYPTSAUDI

ARABIAOMAN

UAE

FRANCE

IRAQ IRAN

SYRIA

TURKEY

PAKISTAN

AFGHANISTAN

INDIA

TURKMENISTAN

UZBEKISTAN

KAZAKHSTAN

SRI LANKA

JORDAN

CYP.

GREECE

LTALY

BUL.BOS.

HUN.

AUS.SWI. M.

UKRAINE

POLANDGARMANY

KUWAIT

QATER

M.

ROMANIA

HOL.

MOROCCO

PORTUGAL SPAIN

RUSSIA

MONGOLIA

INDIA

C H I N A

I N D O N E S I A

A U S T R A L I A

BHUTAN

BANGLADESH

MYANMAR

SRI LANKA

N.KOREA

S.KOREA

JAPAN

TAIWANLOAS

THAILAND

CAMB. VIETNAM

MALAYSIABR.

PAPUA

NEW-GUINEA

NEW-ZEALAND

SWEDEN

EST.

LIT.

LAT.

FINLAND

S.

A.

BELARUS

SOL.

Mali Summary• Active DataFax Studies: 31• DataFax Studies in Setup: 1• Labs: LMIV (Laboratory of Malaria Immunology and

Vaccinology), LMVR (Laboratory of Malaria and Vector Research )

• Study Indications: Malaria, Falciparum, Lassa Fever, M. Africanum TB

• Total CRF pages: 1,290,241

MALI

ICER - Mali

ALASKA (USA)

CANADA

UNITED STATES AMERICA

MEXICO

GREENLAND(DENMARK)

ICELAND

FARCA ISLANDS UNITEDKINGDOM

FRANCE

VENEZUELA CENTRAL

AFRICAN

REPUBLIC

DEMOCRATIC

REPUBLIC

OF CONGO

ALGERIA

NIGERMALI

CHADSUDAN

ERITREA

TUNISIA

MAURITANIA

WESTERN

SAHARA

SENEGAL

GUINEA

LIBERIA

NAMIBIA

ZIMBABWE

ANGOLA

ZAMBIA

BOTSWANA

SOUTHAFRICA

KENYA

TANZANIA

CONOGO

CABON

CAMEROON

NIGERIA

BURKINAFASO

COLOMBOA

GUYANA

SURINAME FRENCHGUIANA

ECUADOR

PERU

BOLIVIA

BRAZIL

PARAGUAY

ARGENTINACHILE

URUGUAY

BELIZEA

HONDURAS

NICARAGUA

GUATEMALA

SALVADORCOSTA RLCA

PANAMA

HAITI DOM.CUBU

BAHAMAS

G.B.

SIERRA L. LVORY

COAST

TOGO

BENION

LES.

SWA.

MADAGASCAR

MALAWI

BU.

SWI.

GARMANYBEL.

NORWAY

DENMARK

ETHIOPIA

JAM.

MOZAMBIQUE

SOMALIA

LIBYA EGYPTSAUDI

ARABIAOMAN

UAE

FRANCE

IRAQ IRAN

SYRIA

TURKEY

PAKISTAN

AFGHANISTAN

INDIA

TURKMENISTAN

UZBEKISTAN

KAZAKHSTAN

SRI LANKA

JORDAN

CYP.

GREECE

LTALY

BUL.BOS.

HUN.

AUS.SWI. M.

UKRAINE

POLANDGARMANY

KUWAIT

QATER

M.

ROMANIA

HOL.

MOROCCO

PORTUGAL SPAIN

RUSSIA

MONGOLIA

INDIA

C H I N A

I N D O N E S I A

A U S T R A L I A

BHUTAN

BANGLADESH

MYANMAR

SRI LANKA

N.KOREA

S.KOREA

JAPAN

TAIWANLOAS

THAILAND

CAMB. VIETNAM

MALAYSIABR.

PAPUA

NEW-GUINEA

NEW-ZEALAND

SWEDEN

EST.

LIT.

LAT.

FINLAND

S.

A.

BELARUS

SOL.

Uganda Summary• Active DataFax Studies: 26• DataFax Studies in Setup: 0• Labs: LMIV (Laboratory of Malaria Immunology

and Vaccinology), LIR (Laboratory of Immunoregulation)

• Study Indications: Malaria, Tuberculosis, HIV, Cryptococcal Meningitis, Syphilis, Liver Cancer, Fibrosis, Lymphoma Non-Hodgkin

• Total CRF pages: 431,060

UGANDA

ICER - Uganda

ALASKA (USA)

CANADA

UNITED STATES AMERICA

MEXICO

GREENLAND(DENMARK)

ICELAND

FARCA ISLANDS UNITEDKINGDOM

FRANCE

VENEZUELA CENTRAL

AFRICAN

REPUBLIC

DEMOCRATIC

REPUBLIC

OF CONGO

ALGERIA

NIGERMALICHAD

SUDANERITREA

TUNISIA

MAURITANIA

WESTERN

SAHARA

SENEGAL

GUINEA

LIBERIA

NAMIBIA

ZIMBABWE

ANGOLAZAMBIA

BOTSWANA

SOUTHAFRICA

KENYA

TANZANIA

CONOGO

CABON

CAMEROON

NIGERIA

BURKINAFASO

COLOMBOA

GUYANA

SURINAMEFRENCHGUIANA

ECUADOR

PERU

BOLIVIA

BRAZIL

PARAGUAY

ARGENTINACHILEURUGUAY

BELIZEA

HONDURAS

NICARAGUA

GUATEMALA

SALVADORCOSTA RLCA

PANAMA

HAITI DOM.CUBU

BAHAMAS

G.B.

SIERRA L. LVORY

COAST

TOGO

BENION

LES.

SWA.

MADAGASCAR

MALAWI

BU.

SWI.

GARMANYBEL.

NORWAY

DENMARK

ETHIOPIA

JAM.

MOZAMBIQUE

SOMALIA

LIBYA EGYPTSAUDI

ARABIAOMAN

UAE

FRANCE

IRAQ IRAN

SYRIA

TURKEY

PAKISTAN

AFGHANISTAN

INDIA

TURKMENISTAN

UZBEKISTAN

KAZAKHSTAN

SRI LANKA

JORDAN

CYP.

GREECE

LTALY

BUL.BOS.

HUN.

AUS.SWI. M.

UKRAINE

POLANDGARMANY

KUWAIT

QATER

M.

ROMANIA

HOL.

MOROCCO

PORTUGAL SPAIN

RUSSIA

MONGOLIA

INDIA

C H I N A

I N D O N E S I A

A U S T R A L I A

BHUTAN

BANGLADESH

MYANMAR

SRI LANKA

N.KOREA

S.KOREA

JAPAN

TAIWANLOAS

THAILAND

CAMB. VIETNAM

MALAYSIABR.

PAPUA

NEW-GUINEA

NEW-ZEALAND

SWEDEN

EST.

LIT.

LAT.

FINLAND

S.

A.

BELARUS

SOL.

India Summary• Active DataFax Studies: 3• Labs: LIR (Laboratory of Immunoregulation), LPD

(Laboratory of Parasitic Disease)• Study Indications: Pulmonary Tuberculosis,

Lymphatic Filarial Disease, Helminth in Latent TB• Total CRF pages: 62,753

INDIA

ICER - India

Required a system that allowed for sequential randomization allocation (allowing stratification) across 9 sites in South Africa and China

01Fixed Randomization

System needed to leverage benefits current provided by IVRS/IWRS.

02 IVRS/IWRS Benefits

The Randomization workflow and data storage had to be seamlessly integrated into the CDMS (DataFax)

03 Integration

Randomization Tool have to comply to various regulations including GCP and 21 CFR Part 11.

04 Compliance

Communication had to be enhanced to become more automated and system driven

05 Communication automation

Reduction in complex user interaction with Randomization Tool as well as reduction in setup requirements (i.e. data mappings)

06 Complexity Reduction

Randomization Tool Requirements

Traditional IVRS/IWRS Challenges

Traditional IVRS/IWRS Challenges

Access to phones, toll-free numbers or ability to phone globally

Language and voice translation requirements - especially for global clinical trials

Technology challenges - especially if complex randomization criteria (e.g. inputtinglaboratory data into IVRS/IWRS or complex study designs influencing randomization)

Time zone challenges and helpdesk availability

Regional settings (e.g. date formatting differences like dd/mm/yyyy vs. mm/dd/yyyy)

Data mapping challenges from the IVRS/IWRS system to the CDMS system

Updates to IVRS/IWRS system – data mapping challenges to the CDMS system

IVRS/IWRS System costs

Additional external data mapping costs (mappings programming and validation into the CDMS)

Traditional Workflow vs. “CDMS” Workflow and quality risks

CDMS (Clinical Data

Management System)

Data Mappings

Sponsor

Monitors

Clinical Drug Suppliers Database

IVRS/IWRS (Interactive Voice/Web Response Systems)

PatientRandomizationby IVRS/IWRS

Data Mappings

Sponsor

Monitors

Clinical Drug Suppliers Database

CDMS (Clinical Data

Management System)

Patient Randomizationby CDMS

PI / Clinician responsible for randomization

QR2

QR1

QR3

QR3

QR1

Quality Risks

QR1 – Using IVRS/IWRS or CDMS systemcorrectly as well as user authentication

QR2 – Data mappings to CDMS (traditionalmodel only)

QR3 – Data reporting / mappings toClinical drug suppliers

Randomization Workflow

Baseline (eDC) Week 4 (eDC) Week 16 (eDC) Randomization Tool (eDC)

Image reviewer Image reviewer Site Study Coordinator Site Randomization Coordinator

Randomization Notifications

Data Manager (Backup)

DataFax(CDMS)

Responsible Person

Data Mapped into Randomization Tool

DataFax Randomization Tool

Baseline and Week 4 Radiology criteria entered via

EDC into CDMS

Week 16 data entered via EDC into CDMS

Randomization to be performed by specific site

users. CDMS will not allow randomization if all criteria

are not met.

Open label randomization arm provided.

Can also be a blinded

treatment number

CDMS Randomization development considerations

Randomization Table development

Randomization table needs to be received, uploaded (as lookup-table) and appropriately protected in the CDMS prior to the database go-live event. User access should be completely restricted and changes should not be allowed. Important to built in controls that disallow any view-access to the Randomization schema

Lookup Table in DFSetup

CDMS Randomization development considerations

Integration of Eligibility criteria into Randomization

CDMS should immediately reject the randomization of patients not meeting the eligibility criteria as entered. This can be done with the use of interactive prompt messages when the user attempts to randomize a patient

CDMS Randomization development considerations

User access management

Users responsible for randomization do not necessary need access to all CRF pages. Access may be restricted to only the Randomization form depending on study needs. System initiated usernames and passwords should be provided for additional level of security during the randomization process.

CDMS Randomization development considerations

Randomization protection

The randomization should be protected after completion (no changes should be allowed onthe form post-randomization).

CDMS Randomization Demonstration

Randomization Tool - Edit Checks

Plate Enter• Map Criteria data from previous

pages• Check if patient is already

randomized (If Patient is already Randomized then make page view-only)

Field Exit• Ensure that all criteria = “Yes”, if

not then do not allow to randomize

Plate Exit• If patient is to be randomized

then invoke dfpassword• Autofill Date (dftoday)• Autofill Time (dftime)• Arm (dflookup)

Randomization Tool Risks

Technology is sufficiently tested before implementation

Randomization workflow/functioning should be tested as part of the CDMS validation

Change control testing

Database changes need to be carefully considered and tested before implementationespecially since randomization functionality may be influenced as a result of other CDMSchanges.

CDMS Downtime

CDMS (DataFax downtime (due to upgrades or other planned outages) should be carefullyconsidered as it may impact randomization activities (which are extremely timely)

Advantages using CDMS (DataFax) for Randomization

Advantages using Data

Reducing the number of system(s) reduces project overhead, validation requirements and project complexities

Study cost reduction

Centralized helpdesk (for CDMS as well as randomization system)

Elimination of separate account details required for IVRS/IWRS systems

Ability to interact/review CRF data (e.g. Screening data) to ensure randomization performed correctly

User authentication per CDMS

Inherent audit trials (including date/time stamps) from the CDMS

Randomization data contained with clinical research data

Acknowledgements

Dr. Clifton E. Barry , Dr. Laura Via, Dr. Ray Chen, Chrissie Cai, Lisa Goldfeder -Tuberculosis Research Section, Laboratory of Clinical Infections Diseases (LCID), NIAID, NIH

Dr. Lori Dodd – Division of Clinical Research (DCR), NIAID, NIH

Lisa Hoopengardner - Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc

Jennifer Xiao, Cindy Lassnoff - NET ESOLUTIONS CORPORATION

Kevin Newell, Christopher Whalen - Research Data and Communication Technologies, Inc.

Alexander Rosenthal, Michael Tartakovsky - 3Office of Cyber Infrastructure and Computational Biology