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