cdm sharvari

8/2/2019 CDM Sharvari

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Sharvari Shukla

BiostatisticianCentre for modeling and simulation, University of Pune

[email protected]

Clinical Data

Management

Module

9
mailto:[email protected]:[email protected]


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Monitoring

Adverseeventreporting

Regulatoryrequirements

QualityControl

Lab

Management

Statistics

Data

Management

CLINICAL TRIAL

OPERATIONS

Recruitment


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What is CDM ?

TERM

CLINICAL

DATA

MANAGEMENT

REFERS TO

CLINICAL TRIAL

DRUG EFFECTS

DOCUMENTATIONANALYSIS and INTERPRETATION


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CDM Definition Clinical Data Management is the process used to

ensure the accuracy and integrity of data by defining

data flow and quality specifications

CDM is skillful handling of clinical trial information

to be used for statistical analysis and interpretation

by ensuring that data is Accurate, Complete andVerifiable


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Basic Research

Clinical Trials Care and Treatment

DataManagement

DATA MANAGERS Product Teams Project Teams Development Teams Multidisciplinary

Team Computerscience

Statistics Life sciences

Research


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Generate Quality Data

1. Complete2. Correct

3. Clean4. Reproducible5. Representative6. Valid

StatisticalAnalysis

AccurateInterpretation

Trial Report

Presentation


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Clinical Data: It is collection of details

from subjects for a particular drug in a

manner which allows its analysis andstatistical interpretation, with the intent to

discover potential beneficial effects and/ordetermine its safety and efficacy


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Click to edit Master subtitle style

Case Report Form Designing


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What is a Case Report Form?

A printed, optical, or electronic document

designed to record all of the protocol required

information to be reported to the sponsor oneach trial subject


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Purpose

Collects relevant data in a specific format- in accordance with the protocol

- compliance with regulatory requirements

Allows for efficient and complete data

- processing, analysis and reporting

Facilitates the exchange of data across- projects and organizations esp. through

- standardization


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Collecting Extra DataExtra Data should not be collected

Is not ethical, as is unnecessary for the protocolfor which participant consented

May create more work for the study coordinator

resulting in longer study visits for theparticipant Results in greater chance for error Creates more work for the statistician as now

more data to be analyzed Takes away the focus from the critical data

points


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CRF and Protocol: Relation

Protocol determines what datashouldbe collected on the CRF

All data mustbe collected on theCRF if specified in the protocol

Data that will not be analyzedshould

notappear on the CRF

Protocol is a BIBLE for any Clinical Trialand

CRF is a TOOL to implement the protocol


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CRF Development: Guidelines

Collect data with all users in mind

Collect data required by the regulatory agencies and outlined

in the protocol

Be clear and concise with your data questions

Avoid duplication

Request minimal free text responses: open ended

Provide units to ensure comparable values

Allow adequate space for response

Use checkboxes wherever possible


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Provide instructions to reduce misinterpretations

Organize CRFs using a combination of visit and type of data

Provide choices for each questions as this allows for

computer summarization

Use None and Not done

Collect data in a fashion that:

- allows for the most efficient computerization

- similar data to be collected across studies

Test and improve the CRF before the trial begins CRF book needs to be finalized and available before an

investigator starts enrolling patients into a study

CRF Development: Guidelines


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Elements of the CRF

Three major parts: Header

Safety related modules

Efficacy related modules Module: block of specific questions CRF module(s) make up single CRF

page


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Header Information

MUST HAVE Study Number Site/Center Number Subject identification number


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Creating Safety Modules

Safety modules are the ones which are used to analyze thesafety of the patient

Select modules appropriate for your study Safety Modules usually include

Demographic Adverse Events Vital Signs Medical History/Physical Exam Concomitant Medications


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Creating Efficacy Modules

Efficacy modules are the ones which are used todetermine the drugs effectiveness

Designed for each therapeutic area based on the protocol Considered to be unique modules and can be more

difficult to develop Design modules following project standards for data

collection Follow general CRF design guidelines Define diagnostics required Include appropriate baseline measurements Repeat same battery of tests Define and identify

- key efficacy endpoints


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Importance of Standard CRFs

Prepares the way for data exchange

Removes the need for mapping during dataexchange

Allows for consistent reporting across protocols,

across projects Promotes monitoring and investigator staff

efficiency

Allows merging of data between studies


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CRF is used for

Subject tracking Data analysis and reporting

Reports to FDA on subject safety New Drug Application submissions

Support of labeling claims


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Flow of CRF Design Process

Reviewers

CRF Designer

CRF Book

Designs CRF from protocol

CRF Review Meeting Comments back to CRF designer

Updates CRF to incl. comments Review and Sign off Coordinate printing and distribution

Site

CRF Designer


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CRF Development Process

After the CRF book is approved Initiate the process for printing

Note: the Protocol must be approved before the CRF book is

approved and printed

After it is printed

Stored according to organizational guidelines

Printed and distributed to research sites


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Members of the CRF development team

representatives of clinical staff,

medical monitors, data entry/management,

ualit assurance and


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Properly Designed CRFs

Components/All of the CRF pages are reusable

Saves time

Saves money

+


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Poorly Designed CRFs

Data not collected Database may require modification

Data Entry process impeded Need to edit data Target dates are missed

Collected too much data Wasted resourcesin collection and processing


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Poorly Designed CRFs

=


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Clinical Database Design


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Data: Information

Database: A structured collection ofrecords or data that is stored in acomputer so that a program can consultit to answer queries

Database


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What is CDMS?

A Clinical Data Management System

is used in clinical research to manage

the data of a clinical trial

The clinical trial data gathered at the

investigator site in the Case Report


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Basic Functions of CDMS

Entry

Store

Validate

Retrieve

Creating Activity Reports


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Purpose of CDMS design

Collects relevant data in a specific format

- in accordance with the CRF

- compliance with regulatory requirement

Allows for efficient and complete data

analysis and reporting


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How this CDMS should be ???

Robust, flexible and powerful option for the studieswho want the data to have double data entry

Quick and easy availability of data entry screens from

a Graphical user interface Edit checks can be run on demand or scheduled to

run at the convenience of the data manager

Ability to handle multiple discrepancies in a userfriendly environment

Flexible reporting capabilities


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Formats of Data

Dates, times: specify format include 24 hrclock if applicable

Numeric data responses Few, if any, text fields Consistent coding (e.g., yes/no) Measurement units (e.g., in/cm, lb/kg, lab

units, dosing units) Option of unknown


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Members of the CDMS design team

Database Designer : Designs the database

Data Entry and Data ManagementPersonnel : Validate the database as per

the CRF


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Widely used CDMS

Oracle Clinical Clintrial Inform OpenClinica

In-house developed systems

D T ki / L i


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Data Tracking / LoggingWhy Track?

Data Management team must produce a database that is:

Accurate, Complete and Verifiable

It should be suitable for analysis by Biostatistics

Data Management may receive data in following formats:

CRF Pages

Lab Reports

Diary Cards etc

What to Track?

D t T ki / L i


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What should be Captured?

Data Management should capture following details:

Who received the data

From whom data was received

When it was received

Details of the data received

For which subject Number of pages received

Missing or Blank pages, if any

Reconcile pages received with transmittal form

Every company has its own data tracking form to capture

above detailsIt ma be electronic or manual

Data Tracking / Logging



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Flagging Tracking Queries?

Tracking person should flag following tracking queries to data cleaningpersonal:

Header information is not consistent on all pages for a subject Initial is not matching on page 1 and page 2

Pages are not in good condition

Number of pages received not match with the transmittal

This may vary from company tocompany




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Data Logging

Data Management should log received data into Clinical Data Management

System (CDMS):

Enter Subject information in CDMS

Enter which all pages are received

Enter whether page is blank or filled


Data Management should be able to generate following reports from CDMS:

Pages received by site, subject Missing page details

Blank page details

D T ki /


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Data Tracking /Logging

Working Copy

sent toData Entry

Original

Stored inArchive

CRF Received

CRF Logged by

Page

Photocopy or

Separate pages

Data Flow


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Protocol

CRF

Data Collection

Database Set-up

Data Logging

Clinical Study Report

Stats Analysis

SAS Programming

Database Lock

Query ManagementData Entry

Data Flow

Data Tracking QC Process


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Data Entry

Possible Methods for Data Entry

Most of CDMS provide following option for data entry :

Independent Double data entry with THIRD PERSON verification

Double data entry with INTERACTIVE verification

Single data entry with MANUAL review

Single data entry with NO review


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Understanding Data Entry

Understanding data entry: process of enteringdata from CRF to response fields in anyCDMS, following certain guidelines/SOPs

CRF

D t E t G id li


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Data Entry Guidelines

Data entry guideline should include

Field by field details on how to enter data

How to enter date, how to enter partial date

How to enter time, how to enter partial time

How to record blank pages

How to handle special characters (@, & sign etc..)

Any general instructions on the study

B f S i i h D E P


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Before Starting with Data Entry Process

Understanding 21 CFR Part 11, that is, Code ofFederal Regulations part 11 chapter 21

FDA defines that persons handling clinical data

have to be sufficiently trained & need to haveelectronic signatures of their own Therefore, each person will have electronic

signature as part of 21 CFR Part 11 compliance

We are all Trainedand we

haveour Elec. Signatures .


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Audit Trail & 21 CFR Part 11

Audit Trail means ... Record of Activities

Data entered, deleted,altered, updated etc.

E-signature help usidentify who did what?


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Data Entry Screen

UNDERSTANDING

DATA ENTRY

RIGHT SIDESCANNED CRF IMAGE

LEFT SIDECDMSSCREEN

CDMS

CRF


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Types of Data Entry

Double Entry

Single Entry


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Data entry

manual verification


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Double data entr

Data entry second data entry

Discrepancies resolved


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Refers to data beingentered to databasefor first time

DEO enters all dataof each document &releases work item

First PassData Entry


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SecondPassData Entry

2

Second pass entry done by another DEO,following first entryThis becomes first quality check in CDMprocessBoth DEO & system contribute to this firstquality check in CDM processSystem gives an alert if second pass entersanything different from first pass

Correct value is confirmed & entered


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Dealing with Different Kinds of Data

DEO (Data Entry Operator) should be aware ofkind of data to be entered

Also, awareness of project specific guidelines &standard guidelines is a must

Data types

DATES/EVENT

S MEDICAL

TERMINOLOGI

ES

NUMERICA

L

DATA

ABBREVIATIONS

GENERAL &

MEDICAL

D

AT

A

DD-MM-YYYY


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Handling Dates ??

Recording dates on case report forms -plays very

integral part DEOs must know different schemes of recording

dates Indians follow dd-mm-yyyy pattern Americans follow mm-dd-yyyy pattern Few European countries follow yy-mm-dd pattern

M di l T i l i


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Medical Terminologies

DEOs should encouragethemselves from beginning toverify (use online sources) & beaware of spellings of variousmedical terminologies

Essential because a slightchange or mis-spelt term canmean totally different

Also, many medical

terminologies have more thanone way of spelling

ReferOnlineSources

Check MySpellingsTwice !!


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During entering data,DEOs have liberty ofentering comments - calledOperator Comments fora particular data point

Operator commentsentered when DEOs are notsure about any illegible text/unclear text

Also, if data is recorded inan erroneous way, operatorcomments can be recorded

InsertComment

If NotSureok

Yes..PointNoted

Stop Entering If NotSure

S T O P !!!

Operator

Comment


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Heads-Up Data Entry

I ReviewData As I EnterData

Also called thinking dataentry personsThey raise a flag when data isillegible for data reviewers or datamanagers

mp y put, t ese entry personne


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Heads-Down enter what they see on CRF Entry faster as they follow natural

flow of CRF

Skill emphasis on number of

keystrokes made and specific

training on database to be utilized

Second pass entry provided after

i l bl


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Single Entry versus Double Entry

FDA & ICH regulations do not require doubleentry or any other specific data entry process

Skill level of resource, time availability and costcontribute to choice of entry process

Double entry helpful where data are subject tofrequent random keystroke errors or where arandom error would be likely to impact the

analysis Single entry with good manual review can be

better than a sloppy double entry one


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Edit Check Programming


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Edit Check - Definition

An auditable process, usually

automated, of assessing the content of a

data field against its expected logical,

format, range or other properties that is

Wh t i Edit Ch k ???


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What is an Edit Check ???

Edit Check = Validation

Validation is the process of checking if something

satisfies a certain criterion

It is important because it disallows data that cannot

possibly be either true or real to be entered into a

database or computer system


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Purpose of Edit Check Programming

It is a tool used for data clean up so as to

ensure that the data which is entered in

the Database is error free and can be

send for analysis


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Where do we define Edit Checks ???

The Edit Check Programmer defines /creates Edit Checks as defined in the Data

Validation Plan

These edit check programs are defined inthe study database


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Types of Edit Checks

Simple Edit Check (Diastolic BP greater than

Systolic BP)

Edit Check with an Arithmetic Function(Difference between Systolic and Diastolic BP >

20)

Complex Edit Check (comparison of onset andresolved date of an Adverse Event)


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Data Clarification Form


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Members of the Edit CheckProgramming team

Edit Check Programmer : Creates the

Edit Check Programs

Data Management Personnel : Validate

the edit check programs as per the Data

Validation Plan

Testing of Edit Check Programs


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EC Programmer writesEC programsReceipt of EC Plan

from DM

DM tests EC programs

EC Program is final andready for production

Testing of Edit Check Programs

Execution o E it C ec Programs


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Execution of EC programs

on production

Review of discrepancies

Update DCF resolution in

DBAll discrepancies are updated

Send DCFs toInvestigator, if required


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Quality Assurance is a process Quality Control is a check of process

Accuracy of data entry checked by auditing

data stored in database against CRF

Ongoing internal and external audits


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Quality Control

Protocol Data Collection Data Processing

Data Analysis CSR

Applied at all steps throughout the trial


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Data that supports conclusions andinterpretations equivalent to those

derived from error-free data


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Advantages of a Data Quality Inspection

Savings on time and money Post db lock, data would be labeled

uncorrectable and excluded from analysis


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How does one improve the quality of data?

Engineer data quality into the process- creating systems that limit the opportunity for

errors Collect only data directly related to the outcome

variable Do it right the first time Do it right

- at the site Remember

data quality is defined at the field!


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Quality must be measured, before

it can be controlled

How does one measure quality?

Error rates


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What are Error Rates?

Error rate = No. of errors / no. of fields inspected

Data quality can be compared across data sets and

across trials

Data quality does not mean -


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Data quality does not mean checkin for ever ossible error

Fields critical to analysis

Identify points with a high frequency of error

Cover data points where a high percentage of error

resolution is possible


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Data Integrity

Data is complete

Data is reliable


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The key to the success of any clinical


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Database closure

Checklist of database closure Generation of final reports

Archiving database and associateddocumentation


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Statistical anal sis

Preparation of Table, graphs and listing Handling of missing values and outliers Scope of evaluation

SAS report generation Statistical analysis and report generation Archiving data and documents


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Thank you

[email protected]

cdm sharvari

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