Clinical Data Management

Sharvari Shukla
Biostatistician Centre for modeling and simulation, University of Pune
sharvareeshukla@hotmail.com Ph-09822414920

Module 9

Recruitment

Monitoring Adverse event reporting Regulatory requirement s

Statisti cs CLINICAL TRIAL OPERATIONS

Data Management

Lab Management

Quality Control

What is CDM ?
REFERS TO TERM CLINICAL TRIAL CLINICAL DRUG EFFECTS DATA DOCUMENTATION MANAGEMENT ANALYSIS and INTERPRETATION

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 and Verifiable

Research
Basic Research

DATA MANAGERS Product Teams Project Teams Development Teams Multidisciplinary Team Computer science Statistics Life sciences

Data Management Clinical Trials

Care and Treatment

Objectives
Generate Quality Data
1. 2. 3. 4. 5. 6.

Complete Correct Clean Reproducible Representative Valid

Statistical Analysis

Accurate Interpretation

Trial Report Presentation

What is Data

Clinical Data: It is collection of details from subjects for a particular drug in a manner which allows its analysis and statistical interpretation, with the intent to discover potential beneficial effects and/or determine its safety and efficacy

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 on each trial subject

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

Collecting Extra Data

Extra Data should not be collected

Is not ethical, as is unnecessary for the protocol for which participant consented May create more work for the study coordinator resulting in longer study visits for the participant 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

CRF and Protocol: Relation

Protocol determines what data should be collected on the CRF All data must be collected on the CRF if specified in the protocol Data that will not be analyzed should not appear on the CRF
Protocol is a BIBLE for any Clinical Trial and CRF is a TOOL to implement the protocol

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

CRF Development: Guidelines

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

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 CRF Book: series of CRF pages

Header Information
MUST HAVE Study Number Site/Center Number Subject identification number

Creating Safety Modules

Safety modules are the ones which are used to analyze the safety of the patient Select modules appropriate for your study Safety Modules usually include Demographic Adverse Events Vital Signs Medical History/Physical Exam Concomitant Medications

Creating Efficacy Modules

Efficacy modules are the ones which are used to determine 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 - additional tests for efficacy

Importance of Standard CRFs

Prepares the way for data exchange Removes the need for mapping during data exchange Allows for consistent reporting across protocols, across projects Promotes monitoring and investigator staff efficiency Allows merging of data between studies Provides increased efficiency in processing and

CRF is used for

Subject tracking Data analysis and reporting Reports to FDA on subject safety New Drug Application submissions Support of labeling claims Articles in medical journals

Flow of CRF Design Process

Designs CRF from protocol

CRF Designer

CRF Review Meeting Comments back to CRF designer

Reviewers

CRF Designer

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

CRF Book

Site

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

CRF Development
Members of the CRF development team

representatives of clinical staff, medical monitors, data entry/management, quality assurance, and

Properly Designed CRFs

Components/All of the CRF pages are reusable Saves time Saves money

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 resources in collection and processing

Poorly Designed CRFs

Clinical Database Design

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Database
Data: Information Database: A structured collection of records or data that is stored in a computer so that a program can consult it to answer queries

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 Form are stored in the CDMS

Basic Functions of CDMS

Entry Store Validate Retrieve Creating Activity Reports

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

How this CDMS should be ???

Robust, flexible and powerful option for the studies who 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 user friendly environment Flexible reporting capabilities

Formats of Data

Dates, times: specify format include 24 hr clock 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

Members of the CDMS design team

Database Designer : Designs the database Data Entry and Data Management

Personnel : Validate the database as per the CRF

Widely used CDMS

Oracle Clinical Clintrial Inform OpenClinica In-house developed systems

Data Tracking / Logging

Why Track? Data Management team must produce a database that is:

Accurate, Complete and Verifiable It should be suitable for analysis by Biostatistics

What to Track? Data Management may receive data in following formats:

CRF Pages Lab Reports Diary Cards etc

Data Tracking / Logging

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 details

Data Tracking / Logging

Flagging Tracking Queries?

Tracking person should flag following tracking queries to data cleaning personal:

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 to company

Data Tracking / Logging

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

Data Tracking / Logging

CRF Received

CRF Logged by Page

Original Stored in Archive

Photocopy or Separate pages

Working Copy sent to Data Entry

Data Flow

Protocol

Clinical Study Report

CRF

Stats Analysis

Data Collection

SAS Programming

Database Set-up

Database Lock

Data Tracking

QC Process

Data Logging

Data Entry

Query Management

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

Understanding Data Entry

Understanding data entry: process of entering data from CRF to response fields in any CDMS, following certain guidelines/SOPs

CRF

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

Before Starting with Data Entry Process

We are all Trainedand we have our Elec. Signatures .

Understanding 21 CFR Part 11, that is, Code of Federal Regulations part 11 chapter 21 FDA defines that persons handling clinical data have to be sufficiently trained & need to have electronic signatures of their own Therefore, each person will have electronic signature as part of 21 CFR Part 11 compliance

Audit Trail & 21 CFR Part 11

Audit Trail means ... Record of Activities Data entered, deleted, altered, updated etc. E-signature help us identify who did what?

Data Entry Screen

UNDERSTANDING DATA ENTRY

LEFT SIDE CDMS SCREEN

CDM S

CRF

RIGHT SIDE SCANNED CRF IMAGE

Types of Data Entry

Double Entry Single Entry

Single data entry

Data entry

manual verification

Double data entry

Data entry second data entry

Discrepancies resolved

Refers to data being entered to database for first time DEO enters all data of each document & releases work item

First Pass Data Entry

Second pass entry done by another DEO, following first entry This becomes first quality check in CDM process Both DEO & system contribute to this first quality check in CDM process System gives an alert if second pass enters anything different from first pass

Correct value is confirmed & entered

Second Pass Data Entry

Dealing with Different Kinds of Data

DEO (Data Entry Operator) should be aware of kind of data to be entered Also, awareness of project specific guidelines & standard guidelines is a must Data types D
DATES/EVENT S MEDICAL TERMINOLOGI ES ABBREVIATIONS GENERAL & NUMERICA L DATA MEDICAL

AT A

DD-MM-YYYY

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

Medical Terminologies

DEOs should encourage themselves from beginning to verify (use online sources) & be aware of spellings of various medical terminologies Essential because a slight change or mis-spelt term can mean totally different Also, many medical terminologies have more than one way of spelling

Refer Online Sources

Check My Spellings Twice !!

Stop Entering If Not Sure

During entering data, DEOs have liberty of entering comments - called Operator Comments for a particular data point Operator comments entered when DEOs are not sure about any illegible text/ unclear text Also, if data is recorded in an erroneous way, operator comments can be recorded

S T O P !!!
Insert Comment If Not Sureok Yes. . Point Noted
Operator Comment

Heads-Up Data Entry

Also called thinking data entry persons They raise a flag when data is illegible for data reviewers or data managers

I Review Data As I Enter Data

Simply put, these entry personnel 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 heads down data entry

Heads-Down Data Entry

Single Entry versus Double Entry

FDA & ICH regulations do not require double entry or any other specific data entry process Skill level of resource, time availability and cost contribute to choice of entry process Double entry helpful where data are subject to frequent random keystroke errors or where a random error would be likely to impact the analysis Single entry with good manual review can be better than a sloppy double entry one

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 intended to reduce error

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

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 Allows for efficient and complete data

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 in the study database

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 and resolved date of an Adverse Event)

Data Clarification Form

Members of the Edit Check Programming 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

Receipt of EC Plan from DM

EC Programmer writes EC programs

DM tests EC programs

EC Program is final and ready for production

Execution of Edit Check Programs

Execution of EC programs on production

Review of discrepancies

Send DCFs to Investigator, if required

All discrepancies are updated

Update DCF resolution in DB

QA-QC

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

Quality Control
Applied at all steps throughout the trial

Protocol

Data Collection

Data Processing

Data Analysis

CSR

What is quality data?

Data that supports conclusions and
interpretations equivalent to those derived from error-free data
Institute Of Medicine

Advantages of a Data Quality Inspection - pre db lock

Savings on time and money Post db lock, data would be labeled uncorrectable and excluded from analysis

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!

Quality must be measured, before it can be controlled

How does one measure quality?

Error rates

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 checking for every possible 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

Data Integrity

Data is complete Data is reliable Data is processed correctly

Quality Data The key to the success of any clinical trial!

Database closure

Checklist of database closure Generation of final reports Archiving database and associated documentation

Statistical analysis

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

Thank you

sharvareeshukla@hotmail.com