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Audits and Inspections

Sponsor Responsibilities
Quality assurance and quality control ...
 ICH GCP Section 5.1.1.
The sponsor is responsible for implementing and
maintaining quality assurance and quality control
systems with written SOPs to ensure that trials are
conducted and data are generated, documented
(recorded), and reported in compliance with the protocol,
GCP, and the applicable regulatory requirement(s).
 ICH GCP Section 5.1.3.
Quality control should be applied to each stage of
data handling to ensure that all data are reliable and
have been processed correctly.

All those planned and systematic actions that are

established to ensure that the trial is performed and
the data are generated, documented (recorded),
and reported in compliance with GCP
and the applicable regulatory requirements.
Quality Assurance (cont‟d)

Proactive Quality Assurance:
* Performing SOP training
Retroactive Quality Assurance:
* Ensure quality by performing
Quality Control (QC)
The Operational techniques and activities undertaken
within the quality system to verify that the requirements
for quality of the trial related activities have been
fulfilled (ICH 1.47)

Operational staff is responsible for

producing quality by:
* working according to SOP‟s
* performing in-process QC
= identify problem and implement
= continuous process / day to day
QA versus QC

Aims to provide Operational means to

confidence in fulfilling the fulfill the quality
quality requirements. requirements

Systematic - continous
Sampling process
What is an audit ?
A systematic and independent examination of
trial related activities and documents to
determine whether the evaluated trial related
activities were conducted, and the data were
recorded, analysed and accurately reported
according to the protocol, sponsor’s SOPs,
GCP and the applicable regulatory
(ICH Section 1.6)
How is audit Different from

Once only' look at site

Covers entire study to that point
Process focus
Observer is independent of conduct of
The sponsor should use appropriately
qualified individuals ( Biostatisticians,
clinical Pharmacologist, and Physicians).
For Public and assurance.
To obtain marketing authorization.- Provide the
evidence of quality

To avoid any litigation.- Costly to pharma industries –

Finance and reputation – Applying the standards –reduce the likelihood of
failure and mitigate the effects of litigation

To make research efficient and cost

effective.- When quality systems are absent – likelihood –
CT false leads and fail to recognize unproductive or even
dangerous direction of Drug development.

To Increase the pride of work.- With quality

standards outlined in GCP provides a safe framework with in which
workers can take pride in their achievements and feed back
suggestions to further enhance the quality of work.
Types of Audits

 Investigator Site
 Local Operating Company (LOC)
 System
 CRO and service providers
 Facilities conducting Early phase studies
Investigator site audit
Feedback will be Site will have the possibility
provided throughout to correct minor deficiencies
the audit during the course of the
+ Advise / Training audit

1 day
files at

Monitor could be asked to be present at site

• As the expert • No Observations Classification at
• For translation purposes closing meeting
• For a smooth/better communication at site • No sharing of audit report
Following GCP (SOP and
Regulatory Requirements)
ensures that sponsor has a
quality clinical research system
Audit of facilities conducting
early phase studies

 Facilities conducting early phase trials

 Internal, Commercial, Hospital, Sites
 The Collaborative studies out of scope
 More detailed review, e.g.
 Safety and emergency resuscitation
 Recruitment (volunteers)
 Site QA Plans
 Facilities (security and restricted access, IP, labs)

 Examination of a process or group of

processes that result in a end product
 Internal system and external vendors/partners
 Reviews of complete departments or a system
within a specific department or function
 Conducted periodically
 Selection based on risk management process
System audit - Examples

 Clinical trial Supplies

 Informed Consent preparation
 Randomisation process
 IDMC (Independent Data Monitoring Committee)
 FDAMA 113 (The Food and Drug Administration
Modernization Act) -protocol posting
 Study Management
 Investigator Brochure
Local Operating Company Audit (LOC)

 Audit of Systems used and studies run by LOC

 Focus on CT and PV/MV
 Frequency: ± every 2 years

 ICH: “A person or organization (commercial, academic,

or other) contracted by sponsor to perform sponsor‟s
trial related duties and functions”
 Also includes other service providers (central IRB‟s,
SMO, Clinical Laboratories, etc)
 To evaluate
• activities performed by the CRO
• systems used by the CRO
• interfaces between Sponsor and the CRO
 to ensure accurate and verifiable data by CRO
Audit Reporting
Audit Observation
An „observation‟ is a discrepancy, error or
deviation from a Policy, SOP, protocol,
authorized written instruction, appropriate
regulation/regulatory expectation or guidelines

3 categories :
Critical : Compromised study
Major : Seriously deviates from standard / prompt
corrective action
Others : Deviates from standard / action
Critical Observation
Validity / integrity of data / product and/or
study conduct / system are compromised.
Critical observations may require that
further operations stop until corrective
action is complete.
The observation has the potential to render
the data for a regulated study, submission,
or facility invalid as it is a deviation from
the regulations and does pose a significant
business risk
Seriously deviates from accepted standard
Requires prompt corrective action
Operations can proceed
May result in regulatory citation

Deviates from accepted standards
Corrective action required
– Within time agreed by owner/auditor
– To improve quality of documents, processes
– To prevent potential decrease in quality or
How to respond to an audit?
Check if the correct Owner identified?
If co-ownership with Central functions
– Study Central Contact or Process Owner or
Department Head
Determine who coordinates responses (usually
How to respond to an audit?
Agree / Disagree to observation

Agree / Disagree to Classification

Planned or completed corrective actions

Person responsible for action

Anticipated timing for resolution

If not possible to change, steps to ensure Obs. not repeated, e.g.

Process Change => SOP/GUID/etc change

Protocol, ICF, IB change
IOP creation
Additional QC

Compliance and training department

can help
Audit Reporting

- 15 +20 (counting
from Draft)

–Do not give report to site

–Monitor’s role to resolve issues
and formulate follow-up actions
on site

– Be placed in study files
– Be kept electronically (email,
personal PC, shared drive) - Except
– Be forwarded to additional
personnel unless there is a specific
Audit Certificates
Confirmation by auditor that audit has
taken place.
Issued for individual study or system
The certificate should make no statement
of degree of compliance noted during the
audit. When filed in the study file it
mentions QA activity but not the audit
One single certificate per study
– Request at least 2 weeks in advance
For cause Investigation
 Significant cause for concern with the conduct of the
trial such that subject safety and/or validity and integrity
of data may be compromised

 Sponsor personnel may suspect “for cause” behavior

by Investigator, site staff, sponsor personnel, contractor
- - Internal and External - -

 During routine monitoring, data handling or routine

For cause Investigation

Clinical Research Fraud

– Generation or deliberate reporting of false
or misleading data with intention to deceive,
or the deliberate withholding of reportable

Serious Misconduct
– Poor study conduct whether intentional or
otherwise, where there is persistent non-
compliance with GCP
Some „For Cause‟ Indicators

 Lack of documentation to confirm eligibility criteria

 No objections against protocol conditions, no
problems during the study, limited knowledge of
 Recurrent difficulties in setting-up an appointment
with the investigator
 Missing documentation or not consistent, abnormal
„clean‟ CRFs, no AEs at all.., difficulties to have
access to patient notes
 Large number of protocol violators
 Drug compliance - either perfect or not done at all
Some „For Cause‟ Indicators
 Results much better than expected
 Diary cards completed with the same pen
 Diary Cards very clean
 Handwriting similarities in subject questionnaires
 Retrospective entries into computer records
 Unusual explanations given to monitor,
investigator extremely evasive
 Variability of data from statistical analysis with
respect to other centres
Some „For Cause‟ Indicators
 Results much better than expected
 Diary cards completed with the same pen
 Diary Cards very clean
 Handwriting similarities in subject questionnaires
 Retrospective entries into computer records
 Unusual explanations given to monitor,
investigator extremely evasive
 Variability of data from statistical analysis with
respect to other centres
How to prevent
 Select only reliable investigators !!!
 Not too busy, not too eager to publish, not primarily
money-consciencious, no limited patient population,
experienced in GCP/CT or willingness to be trained

 Propose clear and feasible protocol, easy CRF

 incl/excl criteria not too complicated, not too many

 Inform the investigator on the possibility to be audited

at any time
How to prevent
 Perform rigorous data monitoring and SDV
 Try to „see‟ the study in action
 Do not „assume‟ ….., verify ! Check that the
investigator knows…
 Take particular attention when studies are conducted
in special situations and where data are easier to
manipulate, where GCP might not be respected, and
where protocol violations or deviations are easily to
introduce (i.e. intensive or surgical care, emergency
What is an Inspection ?
The act by a regulatory authority(ies) of
conducting an official review of documents,
facilities, records, and any other resources
that are deemed by the authority(ies) to be
related to the clinical trial and that may be
located at the site of the trial, at the sponsor’s
and/or CROs facilities, or at other
establishments deemed appropriate by the
regulatory authority(ies).
(ICH Section 1.29)
By external official authorities
Verify, validate, judge
Company reputation at stake
Can have serious business or legal
Inspection Types

- New Product marketing application, part of
– study / project-specific: verify if trial was
conducted, data generated, documented and
reported in compliance w/ protocol, GCP and
sponsor SOPs
Routine GCP
– System inspection: evaluate QA/QC
systems established by sponsor to assure
that trials are conducted and data
generated, recorded and reported in
compliance with protocol, GCP and
applicable reg. requirements
Triggered / directed / for-cause
– complaint
– poor compliance w/ regulatory
Any Questions ?