Clinical Trial Clinical Trial Management Management

& & Part 11 CompliancePart 11 Compliance

Ginger Clasby, MSGinger Clasby, MS

Exec. VP, Business Exec. VP, Business DevelopmentDevelopment

gclasby@promedica-intl.comgclasby@promedica-intl.com

BackgroundBackgroundWhat is Good Clinical What is Good Clinical

Practice?Practice?

A process enabling reliable A process enabling reliable decisions aboutdecisions about

allowing a medical product to be allowing a medical product to be marketedmarketed

Product Approval Product Approval Factors Factors

• Product is safeProduct is safe• Treatment is effective for Treatment is effective for

disease or condition it is meant disease or condition it is meant to treatto treat

Clinical Research Clinical Research Project Principles Project Principles

• Control bias in subject selectionControl bias in subject selection• Compensate for placebo effectCompensate for placebo effect• Reduce examiner biasReduce examiner bias• Objectively compare results to Objectively compare results to

other treatments or controlsother treatments or controls• Produce sufficient statistical power Produce sufficient statistical power

The Study Protocol The Study Protocol • Explains problem & proposes Explains problem & proposes

treatment hypothesistreatment hypothesis• Describes key variables to assess Describes key variables to assess

safety & efficacysafety & efficacy• Specifies & justifies study sample Specifies & justifies study sample

size size • Describes study population Describes study population

The Study ProtocolThe Study Protocol • Identifies exams and allowable Identifies exams and allowable

measurement intervalsmeasurement intervals• Specifies clinical and data endpointsSpecifies clinical and data endpoints• Explains how data collected will be Explains how data collected will be

analyzed analyzed

Study Team Study Team

Study SiteStudy Site

Sponsor/CROSponsor/CRO

Protocol Protocol ImplementationImplementation

• Qualified study sitesQualified study sites• Appropriate equipment & Appropriate equipment &

instrumentationinstrumentation• Adequate training of study teamAdequate training of study team• Appropriate data collection instrumentsAppropriate data collection instruments• Adequate data storage mechanismAdequate data storage mechanism• Adequate study monitoring Adequate study monitoring

Monitoring Study Monitoring Study ProgressProgress

• Subject enrollmentSubject enrollment• Subject accountability at study Subject accountability at study

examsexams• Data recorded & collected Data recorded & collected

Standard Study Data Standard Study Data DocumentsDocuments

• Source documentsSource documents• Data capture forms (CRFs)Data capture forms (CRFs)• Data query forms Data query forms

Source Document Source Document InitialInitial capture of clinical history data, capture of clinical history data,

impressions,impressions,diagnoses and plans of carediagnoses and plans of care

• Hospital recordsHospital records• Clinic/office charts Clinic/office charts • Lab reportsLab reports• Subject DiariesSubject Diaries

Source Document Source Document

Required to substantiate data Required to substantiate data submitted tosubmitted to

sponsor via CRFssponsor via CRFs

Data Capture FormsData Capture Forms

• Case Report Form (CRF)Case Report Form (CRF)• Electronic Data Capture (e-CRF)Electronic Data Capture (e-CRF)

Case Report Form Case Report Form CompletionCompletion

• Formally authorized staff for CRF entries Formally authorized staff for CRF entries • Complete all fields in (black) inkComplete all fields in (black) ink• No unnecessary marks or notations No unnecessary marks or notations • Data changes must not obliterate original Data changes must not obliterate original

entry entry • Changes must be initialed and dated Changes must be initialed and dated • Investigator signs CRFs after finalizationInvestigator signs CRFs after finalization

Data Flow at Data Flow at SiteSiteSiteSite sees subject, records exam data on sees subject, records exam data on

source docsource doc

SiteSite transcribes source data to CRF transcribes source data to CRF

Study monitorStudy monitor verifies data capture & verifies data capture & submits to sponsorsubmits to sponsor

Data Flow at Data Flow at Sponsor/CROSponsor/CRO

Sponsor/CRO Sponsor/CRO enters data to database (#1)enters data to database (#1)

Sponsor/CRO Sponsor/CRO enters data to database (#2) – enters data to database (#2) – “verifies”“verifies”

Sponsor/CROSponsor/CRO visually reviews CRF visually reviews CRF data/logic checksdata/logic checks

Data Query Forms Data Query Forms • After CRFs reviewed by After CRFs reviewed by sponsor/CROsponsor/CRO, further , further

verification or clarification may be required verification or clarification may be required

• Provide traceability regarding data changesProvide traceability regarding data changes

Data QueriesData Queries • Data queries generated by Data queries generated by sponsor/CROsponsor/CRO for for

resolution by resolution by sitesite• Formally authorized staff for query responses Formally authorized staff for query responses • Completed queries must be signed by investigator or Completed queries must be signed by investigator or

authorized staffauthorized staff• Copy of completed data queries filed at Copy of completed data queries filed at sitesite• Query records in Query records in sponsor’ssponsor’s permanent database permanent database

Data QueriesData Queries

Data Query FlowData Query FlowSponsor/CROSponsor/CRO visually reviews CRF data/logic visually reviews CRF data/logic

checkschecks

Sponsor/CROSponsor/CRO generates data query form & sendsgenerates data query form & sends

SiteSite responds to query & returnsresponds to query & returns

Sponsor/CROSponsor/CRO revises database entry as necessaryrevises database entry as necessary

Using Computerized Using Computerized SystemsSystems

in Clinical Trialsin Clinical Trials

General PrinciplesGeneral PrinciplesSystem Definitions System Definitions

• Protocol should identify when Protocol should identify when computerized system is usedcomputerized system is used

• Documentation should identify Documentation should identify hardware & software usedhardware & software used

General PrinciplesGeneral PrinciplesSource Documents Source Documents

• Retain to reconstruct & evaluate Retain to reconstruct & evaluate trialtrial

• Investigators retain originals or Investigators retain originals or certified copiescertified copies

• When original observations entered When original observations entered directly, e-record is “source”directly, e-record is “source”

General PrinciplesGeneral PrinciplesData Accountability Data Accountability

• All info for each subject attributable to All info for each subject attributable to that subjectthat subject

• Record changes shouldn’t obscure original Record changes shouldn’t obscure original infoinfo

• Record changes should be indicated & Record changes should be indicated & means provided to check prior entrymeans provided to check prior entry

• Necessity of audit trail – who changed & Necessity of audit trail – who changed & why?why?

General PrinciplesGeneral PrinciplesThoughtful System Thoughtful System

Design Design • Matches data capture requirements (kg. Matches data capture requirements (kg.

vs. lb.)vs. lb.)• Precludes errors in modification, Precludes errors in modification,

maintenance, archiving, retrieval or maintenance, archiving, retrieval or transmissiontransmission

• Ensures record keeping & retention are Ensures record keeping & retention are in-line with paper systemsin-line with paper systems

General PrinciplesGeneral PrinciplesSecurity MeasuresSecurity Measures

• To prevent unauthorized To prevent unauthorized access to dataaccess to data

• To prevent unauthorized To prevent unauthorized access to computerized systemaccess to computerized system

General PrinciplesGeneral PrinciplesFDA Records AccessFDA Records Access

May inspect all records intended May inspect all records intended to supportto support

submissionssubmissions

e-Data Flow at e-Data Flow at SiteSiteSiteSite sees subject, records exam data on sees subject, records exam data on

source docsource doc

SiteSite inputs data to computer & “commits” inputs data to computer & “commits”

e-Data Flow at e-Data Flow at Sponsor/CROSponsor/CRO

Study monitor Study monitor visually reviews “committed” visually reviews “committed” data vs. “source”data vs. “source”

Sponsor/CROSponsor/CRO reviews CRF data/applies reviews CRF data/applies logic checkslogic checks

Data Processing Data Processing ResponsibilityResponsibility

ActivityActivity PaperPaper EDCEDCGenerate dataGenerate data SiteSite SiteSite

Data inputData input Sponsor/Sponsor/CROCRO

SiteSite

Data verificationData verification Sponsor/Sponsor/CROCRO

Sponsor/Sponsor/CROCRO

Data review & Data review & queriesqueries

Sponsor/Sponsor/CROCRO

Sponsor/Sponsor/CROCRO

Database changesDatabase changes Sponsor/Sponsor/CROCRO

SiteSite

Additional Site Additional Site Qualification QuestionsQualification Questions• Previous experience/comfort level Previous experience/comfort level

with e-data collection activities?with e-data collection activities?• Computer/high-speed internet Computer/high-speed internet

accessibility?accessibility?• On-site technical support On-site technical support

capabilities?capabilities?

Additional Site Additional Site Management PlanningManagement Planning

• Site & subject training and Site & subject training and documentation for e-data capturedocumentation for e-data capture

• Ongoing monitor communication & Ongoing monitor communication & supportsupport

• Technical “Help Desk”Technical “Help Desk”• E-signature managementE-signature management

Add’l Systems Design Add’l Systems Design IssuesIssues

Data EntryData Entry• Prompts for clinical terms & measurementsPrompts for clinical terms & measurements• Prompts for out of range dataPrompts for out of range data• Electronic diaries & e-CRFs designed to Electronic diaries & e-CRFs designed to

allow annotationsallow annotations• Features to facilitate data review & identify Features to facilitate data review & identify

changeschanges• Sponsor access to data during studySponsor access to data during study

Add’l Systems Design Add’l Systems Design IssuesIssues

Electronic SignaturesElectronic Signatures• Individual enters signature at Individual enters signature at

start of data entry sessionstart of data entry session• Attributability of signaturesAttributability of signatures• Passwords changed at Passwords changed at

established intervalsestablished intervals

Add’l Systems Design Add’l Systems Design Issues Date/Time Issues Date/Time

StampsStamps• Controls to ensure correct system Controls to ensure correct system

date/time (yr, mo, day, hr, min)date/time (yr, mo, day, hr, min)• Limited ability (with Limited ability (with

documentation) to change documentation) to change date/timedate/time

Add’l Systems Design Add’l Systems Design IssuesIssues

ControlsControls• SOPs to maintain system integrity SOPs to maintain system integrity in light of changesin light of changes

• Revalidation for changes exceeding Revalidation for changes exceeding operation limits/design specsoperation limits/design specs

• Documentation of software Documentation of software versionsversions• SOPs for contingency plansSOPs for contingency plans

Add’l Systems Design Add’l Systems Design IssuesIssues

ControlsControls• SOPs for backup & recovery of e-SOPs for backup & recovery of e-

recordsrecords• Logs to assess nature & scope of Logs to assess nature & scope of

data loss in the event of system data loss in the event of system failurefailure

• Secure storage of backup recordsSecure storage of backup records

Consider Consider Speed of Data Capture Speed of Data Capture

vs. vs. Costs IncurredCosts Incurred

Clinical Project Clinical Project PlanningPlanning

• Skilled, regularly available technical Skilled, regularly available technical supportsupport

• Detailed hazard/failure analysesDetailed hazard/failure analyses• Skilled, regularly available Skilled, regularly available

monitoring/training supportmonitoring/training support• Increased budget for site participationIncreased budget for site participation• Adequate schedule “padding” for Adequate schedule “padding” for

things to go wrongthings to go wrong