Clinical Trial Management & Part 11 Compliance

Ginger Clasby, MS Exec. VP, Business Development

gclasby@promedica-intl.com

Background What 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 Site

Site 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 sponsors permanent database

Data Queries

Data Query Flow

Sponsor/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 Principles System Definitions

Protocol should identify when computerized system is used Documentation should identify hardware & software used

General Principles Source Documents

Retain to reconstruct & evaluate trial Investigators retain originals or certified copies When original observations entered directly, e-record is source

General Principles Data Accountability

All info for each subject attributable to that subject Record changes shouldnt obscure original info Record changes should be indicated & means provided to check prior entry Necessity of audit trail who changed & why?

General Principles Thoughtful 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 Principles Security Measures

To prevent unauthorized access to data To prevent unauthorized access to computerized system

General Principles FDA Records Access

May inspect all records intended to support submissions

e-Data Flow at Site

Site 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
Generate data
Data input Data verification Data review & queries

Paper
Site
Sponsor/CRO Sponsor/CRO Sponsor/CRO

EDC
Site
Site Sponsor/CRO Sponsor/CRO

Database changes

Sponsor/CRO

Site

Additional Site Qualification Questions

Previous experience/comfort level with edata 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

Addl 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

Addl Systems Design Issues Electronic Signatures

Individual enters signature at start of data entry session Attributability of signatures Passwords changed at established intervals

Addl 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

Addl 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

Addl 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