GCLP: A Clinical Perspective

Hilary Tinsley
Covance Laboratories Ltd.

RQA Conference, Brighton
13 November 2014
Covance ED UK
Work conducted in compliance with GCP:
Receipt, storage & analysis of samples originating from human clinical
trials
(Receipt), management & manipulation data generated from trials
Operating departments
BioAnalytical Small & Large
Clinical Pathology Services
BioPharmaceutical CMC Solutions, Genetic Toxicology, Histology &
Metabolism

Published Guidance Documents
Guidelines on Good Clinical Practice, ICH E6: Good Clinical Practice,
CPMP/ICH/135/95 (July 1996)
EMA reflection paper for laboratories that perform the analysis or
evaluation of clinical trial samples (February 2012)
UK Statutory Instrument 2004 No. 1031: The Medicines for Human
Clinical Use (Clinical Trials) Regulations 2004; plus subsequent
amendments (July 2009)
UK MHRA guidance for the notification of serious breaches of GCP or the
trial protocol (February 2013)
OECD Guidance Document No. 15: Establishment and control of Archives
that operate in compliance with the principles of GLP


Covance ED UK GCP Regulatory Inspection
Experience
Other relevant inspections:
Annual MHRA GLP surveillance inspections
Client QA inspections
~ 50 annually
Aug 2014: Human Tissue Authority inspection
Date Authority Site Scope
Jan 2009 MHRA Harrogate GLP & GCP Site
Jan 2009 US FDA Harrogate Clinical Pathology
Jul 2011 US FDA Harrogate BioAnalytical
Feb 2012 MHRA Alnwick GLP & GCP Site
Feb 2013 US FDA Harrogate Histology
Jul 2013 MHRA Harrogate GLP & GCP Site
Sep 2014 US FDA Harrogate BioAnalytical

Defining GCP requirements
Departments all conducting GLP work
Adhering to principles of GLP many GCP requirements are met:
Provision of suitable facilities
Equipment calibration, use, maintenance and records
Standard Operating Procedures
Data recording practices
Trained technical & scientific staff with associated records
Validation & operation of Computerised Systems



Defining GCP requirements
Additional requirements to meet full compliance, defined in one global
SOP:
Contracts & Agreements
Local Work Instruction
Informed Consent
Sample Management & Trial Subject Confidentiality
Blinding, Un-blinding & Randomisation
Managing Clinically Significant Results
Reporting Analytical Results inc. Expedited Reporting
Managing Serious Breaches
Archiving Data & Clinical Samples
(List of completed GCP studies)
Contracts & Agreements
Definition:
Contractual agreement governing the work to be conducted. Collective
term for Master Service Agreement, Individual Task Order & Local Work
Instruction
Legally binding agreement
Terms & conditions
Revenue generating activities
Study conduct inc. sample receipt, storage, analysis, data manipulation &
reporting requirements
Regulatory Requirements



Contracts & Agreements
Considerations:
Accessibility
Prepared by Contracts group; stored centrally, confidentiality
Document consistency and non-contradictory
Information not exclusive
Non-standard format
Document approval
Contract Termination
Under GCP regulations, for reasons of patient safety, it is essential that
once started, an analytical laboratory is committed to completing the
contracted work
Considerations:
Commercial situation is identified
Risk assessment will be conducted & documented
Where results are critical to patient safety, sample analysis completed


Local Work Instruction
Definition:
Local written work instruction inc., but is not limited to, the purpose of the
analysis, methodology that will be used to perform analysis
Reference relevant clinical trial protocol
Communication of results, blinding/un-blinding results & serious breaches
Define deliverables
Regulatory & QA requirements
Consistent with & does not contradict: contract, clinical trial protocol &
informed consent
Signed by individual responsible for analysis & authorised by Sponsor
Monitor



Local Work Instruction
Considerations:
Accessibility to clinical trial protocol & amendments
Timely
Process when not supplied?
Sponsor Monitor Approval: timely & responsibility
Inconsistencies: resolution
Informed Consent
Requirement of GCP regulations that any person taking part in a
clinical trial must give their written informed consent to participate in
the trial
Considerations:
Demonstrating due diligence
Request generic informed consent
Not received?
Representation from the Analytical Sponsor Monitor
Inconsistencies with contracted sample retention period: resolution
Retention, return or disposition of samples
Visibility to informed consent
Modifications to Work Instruction
Only work that is part of the clinical trial protocol, to which trial subjects
have given consent, must be performed
Additional testing requested by the Sponsor must be documented in an
amendment to the local work instruction
Approved prior to testing
Considerations:
Additional work does not:
Conflict with requirements in the clinical trial protocol
Clinical trial protocol amendment supplied?
Contradict procedures not covered in the trial protocol
Compromise the informed consent
Impact ethics committee approval and/or authorisation given by
competent authority
Timely authorisation

Sample Management & Trial Subject
Confidentiality
Maintaining confidentiality of all persons in a clinical trial is a strict
requirement of GCP & Personal Data Protection Legislation
Each sample uniquely identified using a coded label
Not based on trial subjects name, initials, DOB or other personally
identifiable information
Sample storage & tracking
Samples must be individually accounted for
Sample retention
Sample Management & Trial Subject
Confidentiality
Considerations:
Patient confidentiality breach
All samples should be examined to ensure labels do not facilitate identity
of trial subject
Labelling discrepancy
Request for further analysis?
Storage temperature excursions

Trial Subject Withdrawal
Considerations:
Getting notified
Once notified:
Continue analysis? Report results?
Determine level of consent withdrawal
Request generic informed consent to confirm action and sample fate
Documenting & communicating withdrawal
Full withdrawal, electronic records?
Blinding & Un-blinding
Maintaining the integrity of the blinding process is an essential part of
conducting a clinical trial
If the blinding is compromised the validity of the trial may be put at risk
Considerations:
Establish who is blinded?
Reporting requirements for results
Agree and document
blinding information
communication pathway
Randomisation
For blinded studies, a randomisation code may be supplied as either a
paper record or an electronic version
Codes must only be broken in accordance with the clinical trial protocol
Considerations:
Final version
Secure storage
Received, but not expected?
Managing Clinically Significant Results
Although an analytical laboratory may appear far removed from the trial
subjects, all study personnel have a duty of care to these individuals
Normal ranges for testing should be established prior to analysis
As any anomalous or unexpected result may potentially have safety
implications, all results should be reviewed
Results which indicate clinical significance must be reported to Sponsor
and/or Investigator


Managing Clinically Significant Results
Considerations:
Timely review of results
Investigation
Reporting requirements for clinically significant results
Agree and document
timelines
communication pathway
format
Automated analysers generating additional results beyond scope of local
work instruction


Reporting Analytical Results (inc. expedited
reporting
Robust reporting systems must be implemented:
to control how data is transferred externally
to ensure that the correct data is processed for use in clinical trials
Data may be supplied as hard copy or electronically
Naming data sets
Considerations:
Timely QC of results
Reporting requirements for results
Agree and document
timelines
communication pathway
format
Version control & status
Confirmation intended recipient receives full data set
Managing Serious Breaches
Definition: an issue or deviation which is considered to affect to a
significant degree:
The safety or physical or mental integrity of the subjects of the trial, or,
The scientific value of the trial
In February 2013, the MHRA issued a guidance document on
notification of serious breaches of GCP or the Trial Protocol
Guidance is specific to the UK, however, the description of a serious
breach is similar to the language used in both the ICH E6 Guideline &
EMA reflection paper
Managing Serious Breaches
Considerations:
Raising awareness of potential serious breaches
Documentation, escalation & assessing the breach
Who makes the assessment?
Responsibility for notifying MHRA?
Timelines (should these vary?)

Archiving Data & Clinical Samples
Data transferred to secure Archives & retained for storage period
defined in contract (& in accordance with national legislation)
Clinical samples:
Agreed storage must not exceed storage period defined in informed
consent
Retention in an appropriate facility
In UK, licensed by HTA
At end of storage period, samples either:
Disposed of respectfully
Returned to Sponsor
Archiving Data & Clinical Samples
Considerations:
Maintain full traceability
Document full chain of custody
Transfer to third party
Bio bank retention period for other countries

Finally GCP Regulatory Training
Introductory GCP training
All staff, including staff who generate contracts
Must be completed prior to conducting any GCP regulated work
Annual GCP refresher training
Mandatory
Highlight regulatory changes
Learning objectives; emphasis on basic GCP principles & key areas
identified by QA based on regulatory, client & QA findings
Competency assessment