PROJECT MANAGEMENT: VEGF TRAP CLINICAL
TRIALS
California State University Los Angeles
Winter 2011
Presented by: Sahar Shahiem, Michael DeSalvio, Kevin Ip,
Neha Padwal, Rukshan Thenuwara
Phase 3-Integrated Systems (P3-IS): Who Are We?
• Successful Small Business• $50 million in annual revenues
• Over 20 yrs in PM consulting
• Many areas of expertise in PM • Life sciences, healthcare, biotechnology, medical devices
• Well known for subcontracting clinical trial projects
• Provide distinct deliverables with clear beginning and end
P3-IS – Our Values• We avoid costly delays, inefficiencies and frustrations
No longer worry about: We deliver:
• Miscommunication
• Cross-functional disconnects
• Inconsistent processes
• Competing priorities
• Missing deadlines
• Cut timelines in half
• Objective facilitation
• Precision planning from beginning to end
• Industry best practices
• Improved collaboration
• Skilled PM work on-site
P3 Integrate Systems - VEGF Trap Team
• Mike DeSalvio – Project Manager (PM)• 8 yrs experienced PM• Lead many successful high profile
projects
• Kevin Ip – Assistant PM• 7 yrs exp.• Worked on high profile projects
• Neha Padwal – Clinical Recruitment Manager• 7 yrs exp. in Phase II and III
recruitment• Managed recruitment for many drug
development companies
• Sahar Shahiem – Quality Assurance (QA) & Data Manager• 7 yrs exp. in Phase III clinical trials• Success in quality completion of project
• Rukshan Thenuwara – QA & Risk Analysis Manager • 7 yrs exp. in risk assessment in all
phases of clinical trial
P3-IS Data Collection Complies with FDA Regulations
• Create platform for doc & data management • FDA regulations• 21 CFR Part 11 for Electronic Records & Electronic Signatures
• Comply to Good Laboratory Practice• audit trails, security, data integrity and data archiving.
• P3-IS Document Management functions• fully integrated into the workflow• content and docs may include:
• Analyst certifications, electronic training materials & investigation reports
Fda.gov
Experience in Patient Recruitment
• We have contracts with local nurses & doctors • assist in pt recruitment and observation
• P3-IS dr./nurse requirements• must have 5 years clinical trial experience
• 24 hour on-site availability
Regeneron – VEGF Trap
• Regeneron• Large biotech and biopharm company
• needs help in managing a section of Phase III
• VEGF Trap (Aflibercept)• Blocks new blood vessel growth for
cancer cells
• fusion protein designed to bind to Vascular Endothelial Growth Factor-A (VEGF-A)
• also binds to Placental Growth Factor (PLGF)
Trial Implementation
Contract with PI and Sponsor
Request for Retainer
Preliminary Screening
Review Case Files &
Treatment Documents
First Round
Screening
Schedule Interviews
Patient Authorization
Patient Recruitment
Get Patient Criteria
Determine Sample
Size
Data Collection
Provide Software/Hardware
Install Hardware
Train Users
Server Maintenance
Data Management
Devote Server Space
Implement Server
Security
Establish SQL
Customize Software
Securities EncryptionUser
PermissionsError
Checks
Validation Rules
Schedule Site Networking
Data Hand Off
Meet with Sites
Perform Audit
Verify System Compatibility
Meet with Statisticians
Create User
Access
Securely Transfer
Data
Verify Post Transfer
Data
Unmask Data
Schedule
Task Time Task Cost (k)
Trial Implementation & Initiation
8 d 0m
Pt Recruitment 12-14 w 77k
Data Collection 4.5 w 200k
Data Management 4.5 w 400k
Custom Software for Regeneron
2.1 w 60k
CLINICAL TRIAL FACTS• $1.76 billion out of $8 billion total annual clinical
research spending dedicated to patient enrollment efforts
• 85% trials fail to finish on time- low patient accrual.
• 30% trial sites- Fail in enrolling even a single patient
• 65%- 80% of trials fail to meet their temporal end points.
Cooley, M.E., Sarna, L., Brown, J.K., Williams, R.D., Chernecky, C., Padilla, G., and Danao, L.L. 2003.Challenges of recruitment and retention in multisite clinical research. Cancer Nursing 26(5):376–84.
CLINICAL TRIAL – SET UP• According to Regeneron specifications
• Pts will receive VEGF trap every 3 hours on Day 1• Tx continues for every 2 weeks • for up to 10-15 courses in absence of disease progression or toxicity
• Blood collection- Pharmacokinetic study
• Analysis- Biological markers (VEGF subtypes)• Follow up for 60 days
CLINICAL TRIAL GOALS
• GOAL: To help recruit 4000 adults ages 25-50 years for double blind, placebo controlled trials over 8 month period conducted at sites across U.S
• OBJECTIVE: Evaluate safety and efficacy of VEGF trap• Evaluate angiogenic properties of tissues.
CRITERIA AND SELECTION PROCESS
• Eligibility:• Age- 25- 50 years• Gender: Both• Accept healthy volunteer: No
• Disease characteristics:• Histologically confirmed multiple
myeloma• Relapsed or refractory disease
• Patient Characteristics:• Life expectancy > 14 weeks• WBC > 3000 /mm^3• Not pregnant• No evidence of coagulopathy• No serious traumatic injury within
past 30 days• No known history of allergy to
compounds of similar chemical or biological composition
PATIENT RECRUITMENT DIRECTOR
REGULATORY AFFAIRS DIRECTOR
QUALITY CONTROL MANAGER
CLINICAL MANAGER
REGULATORY STAFF
CLINICAL TRIAL MANAGER
TRIAL SITE COORDINATOR
CLINICAL TRIAL NURSE
PRINCIPLE INVESTIGATOR
SUPERVISOR
HUMAN RESOURCES
DATA MANAGER
PHYSICIAN
ASSISTING STAFF
CLINICAL SUPPLY MANAGER
CLINICALRESEARCH ASSOCIATE
DATAVALIDATION PM
COMMUNICATION PLAN• Bimonthly Video Conferencing amongst Directors.
• Communication Report• Enrollment Status
• Data Quality• Reports- Tracking, Data monitoring, Data management
• Availability of Resources
• Regulation Compliances• Electronic Records, GLP, GCP, cGMP, Quality system regulation• Consent Forms
Audience Type of communication
Mode of delivery Timing of delivery
Authority responsible for delivery
Regeneron Project Status Report Email and Video conferencing
Monthly PI & Supervisor
Regeneron Budget Report Email and Video conferencing
Monthly HR Manager
Regeneron Enrollment Report Email and Video conferencing
Monthly PI & Supervisor
PI & Supervisor Project Status Report Email and Conference Meeting
Bi-weekly Data Manager, Pt Recruitment Director, Clinical Manager, QC
Director
PI & Supervisor Enrollment Report Conference meeting Bi-Weekly Pt Recruitment Director
Data Manager Data Clarity Report E-mail Weekly Data validation manager & Clinical Trial Nurses
Clinical Manager Site investigation Report
Conference meeting Monthly Trial Site Coordinator
Clinical Manager Pt Initial Screening Reports
E-Mail Weekly UC system
Physician Patient Secondary Screening Reports
E-Mail, CRF Weekly Clinical Trial Nurse
Regulatory affairs Director
Regulation Compliance Report
E-mail and Conference meeting
Monthly Regulatory Staff Lead and members
Department Director and or
Supervisor
Conflicts Conference meeting Monthly Team leader having conflicting interests
Risk Management Plan
• Risk management is an ongoing process.• Plan to minimize the probability and impact of adverse
events.• Reference insurance on budget
When a risk is identified the degree of impact:• SCHEDULE• SCOPE• COST• QUALITY
Risk Identification
Risk priority rating of 1,2,3
A risk priority assigned:
1 = significant resources to mitigate
2 = considerable resources to mitigate
3 = less assigned resources to mitigate
Element Ref. Risk Risk Priority
Likelihood (H,M or L)
Impact (H,M or L)
1 Patient Injury 2 L M
Patient Care 2 Patient Attrition 1 H H
3 Data or Property Theft 5 L H
Project Nature 4 Data Loss 3 L H
5 Staff Injury 4 L M
Project Staff 6 Staff Attrition 6 L M
Risk Assessment Chart
Priority Title DescriptionChance
of Impact
Schedule Scope Quality Cost
1Patient Attrition
Loss of pts: death or withdrawal 70% High High High High
2 Patient Injury
Pt injured during tx or clinical site 40% High Low Low High
3 Data LossData is wiped from
servers or individual data
recording devices
10% High High Medium High
4 Staff Injury Staff injured at clinical site
30% Medium Low Medium Low
5Data or Property
Theft
Data stolen from data recording
devices or servers
5% Medium High Medium High
6 Staff Attrition
Resignation or termination of Staff
15% Low Low High Medium
MitigationRisk Mitigation Activity
Patient Attrition• Well established inclusion/exclusion criteria.• Incentives and patient care.• Staff training.
Patient Injury •Patient information sessions/injury reporting •Staff training on injury prevention
Data Loss • Series of drives hardwired to a secure server.
Staff Injury • Insurance policy and training. • Annual facility audits.
Data or Property Theft
• Two identical/separate servers.• Secured wireless uplink to an offsite location
Staff Attrition • Hire trained workers• Staff incentives. • Staff evaluations
Contingency PlanRisk Activity
Patient Attrition •Patients recruited all at once and start simultaneously.
•Patients enter in a “batch” mode.
•Patients are recruited continuously until desired sample size is achieved.
•Patients are recruited until a fixed date is reached.
Patient Injury •Patient evaluation and injury coverage.
•Immediate dismissal from trial if too severe.
Contingency Plan Cont.
Risk Activity
Data Loss • Restore lost data through striping array
Staff Injury • Rehabilitation and time off
• Shift coverage and replacement
Data or Property Theft
• iPads remotely wiped
• Instantaneous backup/lockdown prevent data leaks
Staff Attrition • Subcontract clinical site staffing agency
• Database of qualified candidates
Overview
• Highly regulated due to sensitivity of the data
• Must be masked until stats are performed
• Kept highly secure and encrypted
• Must maintain chain of custody• No compromises
• Puts all data into question
• Track changes and restrict edits
• No single person has full access!
Strategy• Multiple Servers both on and off site• Collected with iPad tablets• Multitude of servers, processors, UPS backups etc.• Tailored to the trial
• Restricted access• Reliable collection
http://www.futt.org/wp-content/uploads/2008/07/server-picture.png
Methods• Installed:
• On site for data storage• Off site for secure backups
• Redundant copies
• Networking• Secure in-house access• Off-site access is contingent• Limits potential for hacks and malicious software penetrations
• Off site storage
http://communities.vmware.com/servlet/JiveServlet/showImage/38-6564-11783/PCoIP+View+Security+Server+1.png
Risks & Mitigation• Data Loss-
• Frequent Backups, backup power sources, redundant drives and striping data recording
• Data Theft-• Server security• SQL security• Encryption on all servers, drives and recording devices• Firewall
• Hacking/ Malicious Software-• Firewall• Encrypted access • Frequent security and IP scans
Contingency• Data Loss-
• Striping allows for lost data to be recovered• Performed on 10 drives, data written across all 10.
• If lost, data can be recovered by server clone• Same drive configuration across 10 drives• Exact clone as the first server• Both kept in-house
• If lost, data can be recovered at off site dual backup• Secured facility, encrypted access only• Confidential location• “Off the grid” and environmentally stable
P3-IS Quality Data Control
• It may seem negligible• BUT small discrepancies can make a significant difference to data
interpretation
• So, data quality control is a must• Especially with data that is used to drive life altering
decisions/conclusions
P3-IS Data Management Control
P3-IS provides scientists and clinicians with:
• Each clinician (2) will have laptops
• can securely store and share complete scientific reports
• Will input data at the same time
• Notification appears if data input is conflicting
• Access codes (login and pw) required
• Everything will be timestamped
• Highlight data corrections, changes etc
Data validation checkpoints (about 5)
• To integrate and analyze correct data input
• practices Good Laboratory Practice
Obtain final authorization on final data
Assistance in correcting errors
• 800 number of program provider
INTEGRATE & ANALYZE
Continue Producing Data Listings
Data Entered into P3-IS program
1st POE Validation by technician
Data Collection (2 clinicans)
P3-IS program datasets Generated
Integrate all data into the datasets
3nd Validation of Clinical Data Review
Adverse Event / Medical Coding
Final Database Review for Completeness get Authorization
Authorization to Deliver Datasets
Data Received
Coding Dept.
Final Data Review for Completeness
Resolution Obtained
Error Identified
2nd Validation Internal Program Check
P3-IS Program Advantage
• Cheaper
• Tables/charts easily pasted into spreadsheets or Word
• Very User Friendly• So training will not be tedious nor
expensive.
• Spreadsheets similar to excel
• Better graphics
• Documentation is better
• Better clarity on algorithms used for statistical procedures
• Good stats analysis (Regeneron)
Our Goal of DM/ Quality Control
• To VALIDATE, VALIDATE, & VALIDATE!
• Recall, Value of the data is only as good as its DM
• Reducing our risk of incorrect interpretations• by increasing quality control
Conclusions
• Meet demands of pt recruitment & data collection
• Practicing GLP
• Subcontracted for section of Phase III• Area I - Patient Recruitment
(~3400 nationwide)
• Area II – Data Collection/Management
• Perform recruitment to clients specifications
• Collect Data
• Manage Data• Maintain integrity • Maintain protection
• Pass off to Statisticians (Regeneron)
• Get Paid!