Principles & Practice of ICH-GCP:

An Investigator's Guide

Dr Rod Owen

Manager, Clinical Trials Unit

Arrowe Park Hospital

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ICH-GCP: An Investigator’s Guide ...

Principles & Practice

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ICH: What does it mean?

International Conference on Harmonisation

(of technical requirements for registration
of pharmaceutical products for human use)

“Tripartite Agreement” between European

Union, United States and Japan (1 May 1996)

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ICH-GCP: ‘EU’ Countries

‘New’ EU = Bulgaria, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania,

Malta, Poland, Rumania, Slovakia & Slovenia; EEA = Iceland, Norway, Switzerland
& Liechtenstein. Note: Canada & WHO are also now ICH signatories 4
GCP: Good Clinical Practice

Ethical and scientific quality

standards for:

Design, conduct, performance,

monitoring, auditing, recording,
analysis and reporting of clinical
trials … and to ensure the rights,
integrity and confidentiality of
trial subjects are protected

ICH-GCP: 1.24

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ICH-GCP: Components

1. Extent of Population Exposure

2. Clinical Safety Data Management
3. Structure and Content of Clinical Trial Reports
4. Dose-Response Data
5. Ethnicity in Clinical Trials
6. Part 6 “Good Clinical Practice” Guidelines
7. Evaluation of Drugs for Use in Geriatric Populations
8. General Considerations
9. Statistics
10. Period Reviews of Safety Data for Marketed Products
11. Evaluation of Drugs for Use in Paediatric Populations
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ICH-GCP: Part 6 GCP Guidelines

Provide public assurance that:

the rights, safety and well-being of trial subjects are

protected by the principles of the “Declaration of
Helsinki”
ICH-GCP 2.1, 2.3

the trial data are credible, and thus acceptable for

mutual acceptance by the regulatory authorities (in
those countries for which the Guidelines were
developed)
ICH-GCP 2.10

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Declaration of Helsinki♣

“Ethical Principles for Medical Research

Involving Human Subjects”
Adopted June, 1964
Amended Tokyo, 1975
Amended Venice, 1983
Amended Hong Kong, 1989
Amended South Africa, 1996
Amended Scotland, 2000
Amendment expected October 2008

♣World Medical Association (WMA) 8

Declaration of Helsinki
(Amended Scotland, 2000)

Significant new Principles:

Protocol to be made public
Results to be made public
Comparator product preferred to placebo
Best treatment identified by study to be given to all
study participants after completion of study

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Declaration of Helsinki
(Tokyo Statement, 2004)

“ The WMA hereby reaffirms its position that it is

necessary during the study planning process to identify
post-trial access by study participants to prophylactic,
diagnostic and therapeutic procedures identified as
beneficial in the study, or other appropriate care.

Post-trial access arrangements or other care must be

described in the study protocol so the ethical review
committee may consider such arrangements during its
review ”

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Belmont Report

“Ethical Principles and Guidelines for the Protection of

Human Subjects of Research”

Three Principles:

Respect of Persons
Beneficence
Justice

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Ethical Principles (1):

Respect of Persons

Treat each subject as autonomous agent

Those with diminished autonomy must be

protected

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Ethical Principles (2):

Beneficence

Subjects must not be exposed to harm

Researchers must maximise any possible

benefits while minimizing possible risks

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Ethical Principles (3):

Justice
Neither wealth nor poverty should be reasons
for the inclusion or exclusion of subjects
who are likely to be beneficiaries of the
research
Subjects must not be selected solely by their
easy availability, compromised position,
manipulability or reasons other than those
directly related to the research
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GCP: EU & UK Legislation

2001/20/EC The “Clinical Trials” Directive

2005/28/EC The “GCP” Directive

Medicines for Human Use (Clinical Trials)

Regulations 2004 [SI 1031]
Medicines for Human Use (Clinical Trials)
Amendment Regulations 2006 [SI 1928]
Medicines for Human Use (Clinical Trials)
No 2 Amendment Regulations 2006 [SI 2984]
Medicines for Human Use (Clinical Trials)
No 3 Amendment Regulations 2008 [SI xxxx] 15
ICH-GCP: An Investigator’s Guide ...

Principles & Practice

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Source Documents

Definition: Original documents, data and

records (eg hospital notes, clinical charts,
laboratory results, pharmacy dispensing
records, X-Rays etc).

Source documents may be originals or may be

copies, microfiches, photographic negatives
once certified as being accurate copies of the
original document
ICH-GCP 1.51, 1.52
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Case Report Form (CRF)

A printed, optical or electronic document

designed to record all of the protocol required
information to be reported to the sponsor on
each trial subject
ICH-GCP 1.11

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CRF: Investigator responsibility

Ensure the accuracy, completeness, legibility and

timeliness of the data in the CRF and all reports
ICH-GCP 4.9.1, 4.9.2

Initial, date (and explain) CRF changes - do not

obliterate the original entry
ICH-GCP 4.9.3

37.4

34.7 RO
28/09/2007
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CRFs: Typical data entry errors

Can you spot the error or errors on this page?

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CRFs: Typical data entry errors

How about this one?

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Valid or fake data?

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Safety Reporting

Adverse Event (AE)

Any untoward medical occurrence, including laboratory
abnormalities, whether or not considered related to the
product, and no matter how minor
ICH-GCP 1.2
*Article 2 (m)

Adverse Drug Reaction (ADR)

Any untoward and unintended medical response to an
investigational medicinal product, and related to any
dose of the product.
ICH-GCP 1.1
Article 2 (n)

*EU Directives: 2001/20/EC & 2005/28/EC

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Safety Reporting

Serious Adverse Event (SAE)

Any untoward medical occurrence that:
results in death
is life threatening (as perceived at the time)

results in persistent disability or incapacity

requires (or prolongs) hospitalisation
is a congenital defect
ICH-GCP 1.50
Article 2 (o)
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Safety Reporting

Suspected Unexpected Serious Adverse Reaction

(SUSAR)

An adverse reaction, the nature and severity of which is not

consistent with the applicable product information
( eg Investigator's Brochure if unlicensed; SmPC if licensed)

ICH-GCP 1.60
Article 2 (p)

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Causal Relationship

Unrelated …
Unlikely to be related …
Possibly related … “Don’t know”
Probably related …
Definitely related …
… to product, device or procedure
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‘Severity’ of Adverse Events

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Adverse Events: Summary
Unrelated Related to IMP

AE ADR

SAE

SUSAR

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Is it a SUSAR?

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Is it a SUSAR? … SmPC … 4.8

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Question 1

A patient gave consent and was entered into a

trial yesterday. This morning the patient took
the first dose of study medication and felt
“severely nauseated” shortly afterwards. The
patient said she was “violently sick” about an
hour later.

AE, SAE, NEITHER?

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Answer 1

2 AEs (nausea, vomiting)

Serious adverse events are not necessarily severe;

“severe” adverse events are not necessarily serious

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Question 2

A female patient, who gave consent and

agreed to practice adequate contraception in
accordance with the study protocol, began
treatment with the trial drug three months
ago. Last week, the patient reported that she
had become pregnant.

AE, SAE or NEITHER?

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Answer 2

SAE or AE … or Neither
ALL pregnancies are usually recorded as SAEs or AEs. This is
the convention. However, unless the Investigator believes
there may be a drug-drug interaction with a contraceptive
drug, it should not be reported as an AE for licensing.

NOTE: A Report of In Utero Drug Exposure (RIUDE)* must

be completed for all pregnancies and sent to the MHRA. The
Sponsor must follow each pregnancy to term, and report
outcome to MHRA (even if birth & baby “normal”).
*Clinical Trial Pregnancy Reporting Form

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Question 3

A patient entered a 6-week study comparing

nicotine patch and nicotine patch plus weekly
counselling for ‘initial-phase’ smoking cessation.
One week after consenting to take part in the
trial, the patient underwent elective repair of a
hernia. The operation was planned to take place
in eight weeks time (ie after the study) but a
cancellation created the opportunity for earlier
surgery, which the patient gratefully accepted.

AE, SAE, NEITHER? 37

Answer 3

NEITHER
The surgical repair of the patient’s hernia was a
planned, elective procedure; the altered date
makes no difference

(The patient’s case notes should show that

diagnosis and schedule for surgery pre-dated
trial entry)
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Question 4

A patient with advanced malignancy consents to

take part in pilot study of a new, patient-operated
device for delivering pain relief medication, and
continues to receive all other medications as per
the Trust’s “standard practice” in Palliative Care.
During the planned 3-week study, the patient
dies from disease progression.

AE, SAE, NEITHER?

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Answer 4

SAE

Although death may well be considered inevitable

for a patient with advanced cancer, and who is
receiving palliative care, death is ALWAYS an SAE

NB: If stated in Protocol, SAEs need not be reported using

the “expedited” procedure – provided MHRA & REC have
agreed
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Adverse Event Reporting

Adverse Event

Serious Non Serious

Unexpected Expected
As per Protocol:
including death
Fatal or Other from progressive
Life threatening disease if MHRA
and REC approve

7 days 15 days Trial report or periodic

safety update

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And finally ...

Call R&D: Extn 2520 (APH) or 4917 (CCO)

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