Highlights from ExL Pharma's Proactive GCP Compliance
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Highlights from ExL Pharma’s Proactive GCP Compliance
March 29-31, 2010Arlington, VA
1
GCP in Emerging RegionsEthics, Quality, and Compliance
The Objectives of Clinical Research
1. To Contribute to Public Health
2. To Contribute to Health Science
3. To Contribute to Economic Development
Good Clinical Practice
A Set of Responsibilities
‘a process that makes all parties to a study responsible for patient safety and study quality’
US & EU Objectives inHarmonizing GCP(3 August 2009, Launch of a Bilateral GCP Initiative)
1. To achieve common understandings and practices
2. To share standards and methodologies
3. To share knowledge4. To share resources5. To improve human
subjects protections
Challenges to GCP Harmonization
1. The extensive reach of clinical trials
2. The complexity of law and regulation
3. Lack of an internationally agreed code of ethics for human research protections
4. The progress of medical science
5. The lack of appropriately representative platforms
Current Ethical Challenges to GCP in Clinical Trials (1)
The use of control arms (placebo)
‘Standard of care’ Informed consent process Community consultation Individual and community
access to research The role & responsibility of
ethics committees (IRBs/ECs)
Compensation for trial injury Patient/Participant
Confidentiality and Privacy Locating phase I, II, and III
trials Pharmacovigilance
Current Ethical Challenges to GCP in Clinical Trials (2)
Medical treatment during the course of research
Product availability Sponsorship Liability & Insurance Tissues Stem Cell Research Data Protection Monitoring (DMCs) Data Ownership Proprietary
Information/Knowledge Publishing Clinical Trial
Information and Results Botanical/Traditional
Medicines
Dimensions of GCP
General Frameworks WHO GCP ICH GCP
Regional/Applied Frameworks EU GCP US CFR
National/Applied GCP Guidelines China, India, Russia,
Singapore, Malaysia, Indonesia, South Korea Argentina, Brazil, Mexico, South America, South Africa, Turkey
The Way Forward for GCP1. Further National & Regional
Development(e.g., CTTI, The AfroGuide Project)
2. A Broader Scope to Include All Health Research
3. Modernizing Guidance to Meet New Developments (e.g., Registries, Results Publication, DMCs, Insurance, Regulatory Science)
4. Appropriate National, Regional, & International Platforms
5. A Broad and Comprehensive Vision Complimented by Small Steps
Proactive GCP ComplianceInvestigator Responsibilities Guidance& A Few Comments on AE Reporting
Supervision of the Conduct of a Clinical Investigation
1. What Is Appropriate Delegation of Study-Related Tasks?
2. What Is Adequate Training?
3. What Is Adequate Supervision of the Conduct of an Ongoing Clinical Trial?
4. What Are an Investigator’s Responsibilities for Oversight of Other Parties Involved in the Conduct of a Clinical Trial?
5. Protecting the Rights, Safety, and Welfare of Study Subjects
CI Responsibilities Guidance
Investigator Longevity(Length of time in active 1572)
Five or More Years25%
Two to Four Years12%
One Year 63%
Source: CenterWatch Analysis 2001
70%
51%41% 36% 34%
30%
49%59% 64% 66%
0%
25%
50%
75%
100%
1994 2000 2004 2006 2008
Shar
e of
Pha
se I
-III
Clin
ical
Tri
als
Affiliated with AMCs Community-Based Investigators
Migration of Clinical Trials into the Private Sector
Standard Operating Procedures
Site Solutions Summit 2009 Survey
Quality Assurance Program
Site Solutions Summit 2009 Survey
Tougher Protocols Harming Performance
Rising number of amendments Number of CRF pages increases from 55 to 180 pages Controlling for treatment duration, cycle times increased
substantially 12% longer protocol readiness to FPFV 70% longer from protocol readiness to data lock
Enrollment rates worsened Screen to randomized dropped from 75% to 59% Randomized to study completion dropped from 69% to 48%
1999-2002(Lower Complexity)
2003-2006(Higher Complexity)
US-based Pivotal Trial Protocols Executed
Who Investigators Believe is Responsible for Compliance FailuresCenterWatch 2002 – FDA Analysis of Notices of Initiation of DisqualificationProceedings Letter
0%
10%
20%
30%
40%
50%
60%
70%
80%
CRASubinvestigatorSelfSponsorCRC/Study Personnel
FDA Assessing Investigators
Whether delegated individuals were qualified to perform such tasks
Whether study staff received adequate training on how to conduct the delegated tasks and were provided with an adequate understanding of the study
Whether there was adequate supervision and involvement in the ongoing conduct of the study
Demonstrate Compliance With Appropriate Delegation
Delegation of Responsibility Log IRB questioning the acceptability of a
persons credentials Sponsors looking more seriously at who
will do what, during the pre site visit Investigator signing off on I/E source
document
But it’s more then a list, it’s knowing who CAN do what and who SHOULD do what
Demonstrate Compliance With Training
Review training records during the pre site visit
Training files – GCP & study specific Which brings up - How many times
must one complete GCP training?
Training tab in each regulatory binder Template to document such training
Demonstrate Compliance With Supervision
Evidence of study staff meetings
Evidence of meetings with sponsor monitor Monitor letter – reviewed, signed and preferably responded to PI & CRA meeting minutes*
Set of SOPs to Guidance requirements & GCPs
Evidence of Investigator involvement in the study Appropriate signature on lab results Signature on I/E source documentation worksheet AE assessment (causality & severity)*
Protecting the Rights, Safety and Welfare of Study Subjects
Review treatment of, and follow-up of SAEs/AEs (sponsor's protocol/policy)
Evidence of subject's Primary Care Physician having been informed (with subject's consent)
Evidence of Investigator's presence throughout the study
Adherence to protocol
AE Reporting
“IRBs raise concerns related to the increasingly large volumes of individual AE reports submitted to the IRBs – often lacking in context and details…”
Investigators still get these “large volumes of reports, often lacking in context and details”
Reporting of unanticipated problems to the IRB by the Sponsor… “because the investigator, Sponsor, and IRB made an explicit agreement…”
Which of these industries do you think are generally honest and trustworthy?
2%
3%
4%
7%
7%
9%
14%
16%
23%
28%
31%
34%
Tobacco
Oil
Managed Care
Health Insurance
Pharmaceuticals
Automobile
Gas and Utilities
Airlines
Computer Software
Hospitals
Banks
Supermarkets
Source: Harris Interactive Inc, 2007
Percent Agree
Site Report Card
Site Solutions Summit 2009 Survey
Ask For What You Want
Site Solutions Summit 2009 Survey
Proactive GCP Compliance
Overview The typical reaction to a finding from a
Good Clinical Practice (GCP) audit or inspection is a quick fix to:
› Update the wording in a Clinical Standard Operating Procedure (SOP), or
› Provide more training
But this does not guarantee that the:
› Process will be more effective,› SOPs will be followed, or that › Activities will prevent similar issues from
occurring
Overview To have sustainable compliance across
clinical trials, a set of underlying mechanisms should be in place for:
› Building effective clinical processes, › Managing continuous improvement, and › Holding staff accountable for day to day
quality and compliance
Overview These mechanisms provide a framework for
the:
› Collection, identification and prioritization of compliance issues,
› Use of root cause analysis (RCA),› Implementation of proposed
corrective/preventative actions (CAPAs), and › Change in culture needed to effectively support,
govern, measure, communicate and train on compliance driven activities
Collectively, these are the foundation for developing and implementing a Quality Management System (QMS) for GCPs
Cost of Quality All products and
services have a cost of quality
Reactive models rely on rework at end of project
Proactive models enable quality to be “built in” through prevention:› Lower overall costs› Better compliance› Less rework/resources needed› Fewer audit/inspection findings
& less severe ratings› More timely submissions› Better perception/reputation
with regulatory agencies
0
20
40
60
80
100
120
140
160
180
200
ReactiveModel
ProactiveModel
ReworkCosts
DetectionCosts
PreventiveCosts
$ Million•Illustrative numbers to show cost differences • not intended to imply actual costs
Prevention Costs + Detection Costs + Rework Costs = Total Cost of Quality
The Focus – Clinical Trial Operations
33
SOPs
MonitoringTMF
Training
ComplianceActivities
Process ManagementActivities
Implementation ActivitiesFoundation Processes
Clinical / Service Processes
The Foundation Processes
Mar 30, 2010
How to manage initiatives and process changes effectively
Process Mgmt Activities
Plan
How to proactively build lessons learned, improvements,
new skills, management
involvement and measures of success into organization
ImplementationActivitiesDo
How to collect,
report, trend and
prioritize issues and
propose changes /
resolutions on global
basisComplian
ceActivities
Assess
Roles and Accountabilities
Clinical / Service
Staff
Quality / Complianc
e Staff
Governance / CI Teams
RA/Auditing
Staff
Quality Control (QC):Daily hands on activities to ensure operations and associated deliverables meet quality standards and metrics
Quality/Compliance:Oversight for process development, inspection readiness, compliance oversight, continuous improvement, quality metrics, compliance communications and engine for QMS
Management Support / Governance/CI:Oversight of strategic direction of compliance activities, tactical assessments, priority of issues, measurement/ enforcement of compliance and implementation of CAPA/process improvements
Research into, implementation of and support for compliance issues, proposed changes and expected outcomes
Audit:Independent examination by sponsor or contracted resource to determine whether the sampled trial activities were conducted, recorded, analyzed and reported according to all requirements
Oversight of regulatory inspections
Roles: Governance/CI Teams
= =
Clinical/Service Processes
Foundation Processes
ProcessTeamProcessTeamProcessTeamProcessTeamProcessTeamProcessTeamProcessTeamProcessTeamProcessTeam
ProcessTeam
InitiativesCAPAs
PoliciesSOPsGDs
SystemsTraining
Mgmt Sponsor
Process Lead(s)
Process SMEs
Training Rep
ProcessTeamProcess
TeamProcessTeam
ProcessTeam
InitiativesCAPAs
PoliciesSOPsGDs
SystemsTraining
Assessment Board
Cost Time
Quality
Executive Governance
Root Cause Analysis needs to follow a systematic process
Inadequate Data (4%)
Poor Prioritization (11%)
Incorrect Decision Making(27%)
Adaptive not Corrective Actions (15%)
Faulty Problem Solving (43%)
Proper Problem Resolution Define the Problem Collect Data Identify Possible Causes Identify Root Causes Recommend and Implement
Solutions
Tools for RCA capture and articulate the logic of deviation’s causes
Structures Investigation Brainstorm the issues Flowcharting Fishbone Analysis – Cause /Effect Diagrams 5 Whys technique Force Field Analysis Pareto Charts Run Charts Six Sigma Analysis (DMAIC)
Structured Investigation Method
1. Define the performance problem (DEFINE)
2. Collect Existing Data (MEASURE)
3. Identify Possible Causes (ANALYZE)
4. Test Possible Causes (ANALYZE)
5. Identify Root Causes (ANALYZE)
6. Determine Best Solution (IMPROVE)
7. Verify Solution (CONTROL)
Tools such as Fishbone diagrams provide focus
Measurement Procedures People
Problem
SitesPolicyEnvironment
Best used at the beginning of the root cause analysis process Usually a team activity; allows for different points of view Expands the scope of the investigation; mitigates against focusing
/ targeting too soon Identifies areas that need further analysis (e.g., review of data,
experimentation); does not pinpoint root cause.
Fishbone Diagram - Example
Wrong Kits assembled and sent to investigation sites
Process Training
Human
Validation done at Lab Supplies, Lab kits sent from distribution for re-assembly and distribution
No adequate training to staff regarding the new lab kits
Miscommunication between sites
Inattention to work order requirements
Major cause
categories
Root cause
Summary: Potential Ways to Improve/Ensure Compliance
Compliance Issues Develop compliance objectives/metric Routinely perform analyses for recurring trends Prioritize and work on trends with biggest impact/risks Shift focus from reporting issues to understanding causes Implement cross-functional process improvements/lessons learned
Staff/Culture Assess, and increase, dedicated compliance resources, as needed Promote resolutions across programs Hold staff accountable through evaluations/ratings Promote error free culture Develop and implement effective communications of
issues/solutions Add temp resources to complete backlog of process
improvements/SOPs
Summary: Potential Ways to Improve/Ensure Compliance
Organization Implement software for documenting, tracking and training on
processes Establish effective compliance forums / governance committee(s) Centralize oversight / tracking of process improvement initiatives
and link to SOP updates
Process Transition from SOP training to effective learning across processes Build QC steps into all future process changes Add temp resources to complete backlog of process
improvements/SOPs Restructure Initiative/SOP teams Measure success of current changes prior to more being made
Still have any questions? For additional information on ExL Pharma’s Proactive
GCP Compliance Conferences, please visit www.exlpharma.com
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