Clinical Trial Management

& Part 11 Compliance

Ginger Clasby, MSExec. VP, Business

Developmentgclasby@promedica-intl.com

BackgroundWhat is Good Clinical

Practice?

A process enabling reliable decisions about

allowing a medical product to be marketed

Product Approval Factors

• Product is safe• Treatment is effective for

disease or condition it is meant to treat

Clinical Research Project Principles

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

other treatments or controls• Produce sufficient statistical power

The Study Protocol • Explains problem & proposes

treatment hypothesis• Describes key variables to

assess safety & efficacy• Specifies & justifies study

sample size • Describes study population

The Study Protocol • Identifies exams and allowable

measurement intervals• Specifies clinical and data

endpoints• Explains how data collected

will be analyzed

Study Team

Study Site

Sponsor/CRO

Protocol Implementation

• Qualified study sites• Appropriate equipment &

instrumentation• Adequate training of study team• Appropriate data collection

instruments• Adequate data storage mechanism• Adequate study monitoring

Monitoring Study Progress

• Subject enrollment• Subject accountability at study

exams• Data recorded & collected

Standard Study Data Documents

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

Source Document Initial capture of clinical history data,

impressions,diagnoses and plans of care

• Hospital records• Clinic/office charts • Lab reports• Subject Diaries

Source Document

Required to substantiate data submitted to

sponsor via CRFs

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

CRF)

Case Report Form Completion

• Formally authorized staff for CRF entries

• Complete all fields in (black) ink• No unnecessary marks or notations • Data changes must not obliterate

original entry • Changes must be initialed and

dated • Investigator signs CRFs after

finalization

Data Flow at SiteSite sees subject, records exam data on

source doc

Site transcribes source data to CRF

Study monitor verifies data capture & submits to sponsor

Data Flow at Sponsor/CRO

Sponsor/CRO enters data to database (#1)

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

Sponsor/CRO visually reviews CRF data/logic checks

Data Query Forms • After CRFs reviewed by

sponsor/CRO, further verification or clarification may be required

• Provide traceability regarding data changes

Data Queries • Data queries generated by

sponsor/CRO for resolution by site• Formally authorized staff for query

responses • Completed queries must be signed

by investigator or authorized staff• Copy of completed data queries

filed at site• Query records in sponsor’s

permanent database

Data Queries

Data Query FlowSponsor/CRO visually reviews CRF

data/logic checks

Sponsor/CRO generates data query form & sends

Site responds to query & returns

Sponsor/CRO revises database entry as necessary

Using Computerized Systems

in Clinical Trials

General PrinciplesSystem Definitions

• Protocol should identify when computerized system is used

• Documentation should identify hardware & software used

General PrinciplesSource Documents

• Retain to reconstruct & evaluate trial

• Investigators retain originals or certified copies

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

General PrinciplesData Accountability

• All info for each subject attributable to that subject

• Record changes shouldn’t obscure original info

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

• Necessity of audit trail – who changed & why?

General PrinciplesThoughtful System

Design • Matches data capture requirements

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

maintenance, archiving, retrieval or transmission

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

General PrinciplesSecurity Measures

• To prevent unauthorized access to data

• To prevent unauthorized access to computerized system

General PrinciplesFDA Records Access

May inspect all records intended to support

submissions

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

source doc

Site inputs data to computer & “commits”

e-Data Flow at Sponsor/CRO

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

Sponsor/CRO reviews CRF data/applies logic checks

Data Processing Responsibility

Activity Paper EDCGenerate data Site Site

Data input Sponsor/CRO

Site

Data verification Sponsor/CRO

Sponsor/CRO

Data review & queries

Sponsor/CRO

Sponsor/CRO

Database changes Sponsor/CRO

Site

Additional Site Qualification Questions• Previous experience/comfort

level with e-data collection activities?

• Computer/high-speed internet accessibility?

• On-site technical support capabilities?

Additional Site Management Planning

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

• Ongoing monitor communication & support

• Technical “Help Desk”• E-signature management

Add’l Systems Design Issues

Data Entry• Prompts for clinical terms & measurements

• Prompts for out of range data• Electronic diaries & e-CRFs

designed to allow annotations• Features to facilitate data review &

identify changes• Sponsor access to data during study

Add’l Systems Design Issues

Electronic Signatures• Individual enters signature at start of data entry session

• Attributability of signatures• Passwords changed at

established intervals

Add’l Systems Design Issues Date/Time

Stamps• Controls to ensure correct system date/time (yr, mo, day, hr, min)

• Limited ability (with documentation) to change date/time

Add’l Systems Design Issues

Controls• SOPs to maintain system integrity in light of changes

• Revalidation for changes exceeding operation limits/design specs

• Documentation of software versions• SOPs for contingency plans

Add’l Systems Design Issues

Controls• SOPs for backup & recovery of e-records

• Logs to assess nature & scope of data loss in the event of system failure

• Secure storage of backup records

Consider Speed of Data Capture

vs. Costs Incurred

Clinical Project Planning

• Skilled, regularly available technical support

• Detailed hazard/failure analyses• Skilled, regularly available

monitoring/training support• Increased budget for site

participation• Adequate schedule “padding” for

things to go wrong