quality tolerance limits - · pdf file©eucrof, d. chase, m. garot 3 london, 22 may 2012...

1 London, 22 May 2012 © EUCROF, D. Chase, M. Garot

Workshop GCP IWG - Interested Parties on the Reflection Paper on Risk Based Quality Management in Clinical Trials

EMA

London

22 May 2012

Dr. Dagmar Chase, Vice President EUCROF

Dr. Michèle Garot, EUCROF Representative

Quality Tolerance Limits


Outline

Tolerance Limits in Clinical Trials - Introduction

- Examples of different types

- Definitions

What tolerance limits mean for clinical trials

- Areas

- Per protocol vs per GCP

- Who will set them up?

- When will they be set up?

- Where will they be set up?

What we might gain

Limitations and Challenges


Tolerance Limits – Examples

Value Driven

Upper Limit

Lower Limit

SpecificationAcceptableQuality

Range

Different types

• Zero tolerance Measurement exactly 60 min post dosing

• One sided tolerance Minimum infusion duration of one hourDatabase acceptance: 99,5 % correctnessSAE Reporting: immediately 24 hrs

Control visit: Day 7 + 1 day

• Two sided - symmetric Control visit: day 14 +/- 2 days

• Two sided - asymmetric Drug accountability: 85% – 105 %

Combination of different types over time might be applicable



Event Driven

Occurrence of an unwanted event / situation

Recurrence of an unwanted event / situation

….

Trigger an

action plan

(mitigation) or

FULL STOP

Missed or latereporting of an SAE

Caution!

Be aware

and inform



Event Driven



….

Trigger an

action plan

(mitigation) or

FULL STOP

Caution!

Be aware

and inform

Missed or latereporting of an SAE



Event Driven



….

Trigger an

action plan

(mitigation) or

FULL STOP

Caution!

Be aware

and inform

RandomisationError


• Source data not complete

according to specification

• Randomization

error


Event Driven



….

Trigger an

action plan

(mitigation) or

FULL STOP

Caution!

Be aware

and inform


Example:

Distribution / Threshold Driven

Premature terminations above protocol average

Is there an unusuallyhigh drop-out rate at any site?

* * * * * * * *

Threshold:1.3 x Ø

Clinical Trial Centers

Protocol Ø

Risk Indicator: Premature termination of patients

Measures the drop-out rate per site against the protocol average

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ut

pe

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ati

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sit

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ag

ain

st

the

pro

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ol

av

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Ref.: Beat Widler


Definitions

Tolerance

The unwanted but acceptable deviation from a desired dimension. The tighter the tolerance, the greater the cost to

“manufacture the part”(Ref.: www.toolingu.com)

Tolerance Limit

In quality control, the limiting values between which measurements must lie if an article is to be acceptable, … . (Ref.: OECD)

Design Space

The multidimensional combination and interaction of

input variables and process parameters that have been demonstrated to provide assurance of quality (Ref.: ICH-Q8)


Outline



- Definitions


- Areas





What we might gain



Areas of Tolerance Limits

Trial Management(Decision Making)

Metrics / Trigger Setting

• Monitoring• Monitoring visit frequency• Extent SDV• Extent central monitoring

• Data management• Query rate• Query turn around time• DB validation

• Safety• Missed or late SAE reporting

• IMP management• Temperature excursions

• Randomization / blinding issues

Implementation/Tracking/Controlling(Decision Making / Changing)

• Status reports, event / protocoldeviation review, data distributions

• Change Trial Procedures• Change Data Specifications

Trial Procedures

(Compliance)

Protocol

GCP / Reg. Requ. / SOPs Efficacy Parameters

Trial Data(Specifications)

• Measurement/ Collection (Precision, Accuracy)

• Timing• Recording / transcription

• Consider importance inrelation to trial objectives

• Input for trial procedures

Safety Parameters

Other Data, e.g., Inclusion / ExclusionCriteria

• On-site Monitoring• SDV (ICF, Data)• IMP management• Sample management• SAE reporting• Investigator File• Randomization and blinding• Facilities and equipment• Site personnel qualification

• Central Oversight• Safety / efficacy data review• Centralized monitoring• Reconciliation of data from

different systems (Clinical DB, CTMS, IxRS, lab data, safety DB…)• Edit checks (Data management)• Data distributions (Statistics)


Tolerance Limits:

Per protocol vs per GCP

Examples from protocol

Acceptable time windows for study assessments (visits) are as follows : Screening, D1-3: zero;D7 + 1 day; D14 ± 2 days; D28 ± 2 days; D42 ± 7 days; Day 84 ± 7 days; Every 4 Weeks until EOT / Day 180 ± 7 days;

Blood sampling for PK sub-study, performed either on Day 7 or preferably Day 14

The patient will be given a minimum of 24hrs to consider and confirm participation by signing the IC

Average frequency of monitoring visits to each site will be linked to the presence of actively participating patients and is likely to be approximately every 6 weeks at sites with actively participating patients

Protocol

Protocol

GCP /

Protocol

GCP /

Protocol


Tolerance Limits:Who will set them up?

When will they be set up?

Trial Management(Decision Making)Trial Procedures

(Compliance)Trial Data

(Specifications)

Sponsor

Dev. Program Lead

Pre-clinicalGMP

Medical / ExpertsBiostatistician

Investigator

MDRadiologist

LabCentral services

Pharmacy

Sponsor (CRO)

Clinical Trial Manager

(GCP Expertise)

Independent

Committees

Before FSI During run-timeDuring Trial /

Protocol Design

Sponsor (CRO)

Clinical Trial Manager(GCP Expertise)MonitoringSafetyIndep. CommitteesGMPData ManagementEDCIxRSBiostatistician


Ris

k M

an

ag

em

en

t T

oo

ls

RISK REVIEW

Ris

k C

om

mu

nic

atio

n

Output: Final (Risk Management)Report

Inititiate Risk BasedQuality Management Process

Are the Risksacceptable

no

yes

Collect (new) Information(Systems, Dev. Program,

Clinical Trial)

Report onRisk Control

Define Risk MitigationAccording to Acceptance

Level and Write/Revise RM Plan

Identify, Analyseand Evaluate Risks

Implement (Revised) Risk Mitigation Plan

TrialOngoing

no

yes

Review Events

RISK ASSESSMENT

RISK CONTROL

Lessons learned

from other trials

Tolerance

Limits

Setting /

Monitoring


SOPs

SOPs

Tolerance Limits:

Where will they be set up?

Trial Management(Decision Making)Trial Procedures

(Compliance)

Protocol

Trial Data(Specifications)

Trial specific

Plans• Monitoring

• IMP Management

• Data Management

• Statistical Analysis

• Safety

• CRO Oversight

• Audit

…

• Quality Manual

(Risk Mitigation

Plan, RMP)

Amendments/

Updates to

• Protocol

• Trial specific

plans

• Quality Manual

(RMP)

Quality Report

(Risk Management

Report)


Outline



- Definitions


- Areas





What we might gain



What we might gain

Simplified processes and procedures where justified

Improved practicability, protocol and GCP compliance

Increased focus on risks/ protocol deviations which may impact subject safety and study objectives

Less protocol deviations and possibly less protocol amendments

Higher quality plus

Cost Savings

• Simplification

• Practicability

• Increased

robustness

Use of resources where

they are really needed



Scientific validity

- Medical

- Statistical (power of the trial)

Subjects’ safety

Qualified personnel

Integrated systems / tools / real time data capture

Resistance to change at Sponsor / CRO

Acceptance of sponsor decisions regarding

tolerance limits by regulators ? ? ?

Thorough documentation of the decision making


Thank you very much for your attention

quality tolerance limits - · pdf file©eucrof, d. chase, m. garot 3 london, 22 may 2012...

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