GCP in the EU

Good Clinical Practice in the European Union

The History

1946 Code of Nürnberg

1964 Declaration of Helsinki

1979 Belmont Report

Good Clinical Practice in the European Union

The History

In the Nineties:

EU-GCP Guideline
Nordic Guidelines
ICH-GCP-Guideline
WHO Guidelines
CIOMS Guideline
EU-Note for Guidance on GCP
Good Clinical Practice in the European Union

The 13 Principles of ICH – GCP

1. Clinical trials should be conducted in accordance with the

ethical principles that have their origin in the Declaration of
Helsinki, and that are consistent with GCP and the
applicable regulatory environment(s).

2. Before a trial is initiated, foreseeable risks and

inconveniences should be weighed against the anticipated
benefit for the individual trial subject and society. A trial
should be initiated and continued only if the anticipated
benefits justify the risks.
Good Clinical Practice in the European Union

The 13 Principles of ICH – GCP

3. The rights, safety, and well-being of the trial subjects are
the most important considerations, and should prevail over
the interests of science and society.

4. The available non-clinical and clinical information on an

investigational product should be adequate to support the
proposed clinical trial.

5. Clinical trials should be scientifically sound and described

in a clear, detailed protocol
Good Clinical Practice in the European Union

The 13 Principles of ICH – GCP

6. A trial should be conducted in compliance with the

protocol that has received prior institutional review board
(IRB) / independent ethics committee (IEC) approval /
favourable opinion.

7. The medical care given to, and medical decisions made on

behalf of, subjects should always be the responsibility of a
qualified physician or, when appropriate, a qualified
dentist.

8. Each individual involved in conducting a trial should be

qualified by edcuation, training, and
experience to perform his or her task(s).
Good Clinical Practice in the European Union

The 13 Principles of ICH – GCP

9. Freely given informed consent should be obtained from

every subject prior to clinical participation.

10. All clinical trial information should be recorded, handled

and stored in a way that allows its accurate reporting,
interpretation, and verification.

11. The confidentiality of records that could identify subjects

should be protected, respecting the privacy and
confidentiality rules in accordance with the applicable
regulatory requirements.
Good Clinical Practice in the European Union

The 13 Principles of ICH – GCP

12. Investigational products should be manufactured, handled,

and stored in accordance with applicable good
manufacturing practice (GMP). They should be used in
accordance with the approved protocol.

13. Systems with procedures that assure the quality of every

aspect of the trial should be implemented.
Good Clinical Practice in the European Union

The History

2001 Clinical Trials Directive

2002 Detailed Guidance's

2005 GCP Directive

 Good Clinical Practice in the European Union

The New Regulatory Environment for

Clinical Trials
♦ Directive 2001/20/EC (’Clinical Trials Directive) has
come into force May 1, 2004
♦ 6 related Guidances available, partly updated
♦ Annex 13 GMP for Trial Medication,
released July 2003
♦ Directive 2003/94/EC (‘GMP Directive’) released
Oct 8, 2003
♦ Directive 2005/28/EC (‘GCP Directive’)
released April 8, 2005
Good Clinical Practice in the European Union

The 6 related Guidances

♦ European clinical trials database (EudraCT)

♦ The application format and documentation to be submitted
in an application for an EC opinion on a clinical trial

♦ The request for approval of a clinical trial to the CA in EU,

notification and approval of Substantial Amendments and
declaration of end-of-trial
Good Clinical Practice in the European Union

The 6 related Guidance's

♦ European database of SUSARS (EudraVIGILANCE-Clinical

Trial Module)

♦ Safety reporting
♦ IMPs and other medicinal products in CTs
♦ (Guideline on special modalities for non-commercial CTs
under discussion)
Good Clinical Practice in the European Union

Objectives of Directive 2001/20/EC

♦ To ensure clinical trial subjects’ protection of human rights
and dignity, especially those not able to consent

♦ To ensure compliance with GCP for ALL trials with an

Investigational Medicinal Product, and GMP for
Investigational Medicinal Products (IMP) (incl. placebo)

♦ To define Europe-wide harmonized procedures and time

frames for Competent Authorities (CA), Ethics Committees
(EC), and sponsors (initiation, conduct and surveillance of
studies)
 Good Clinical Practice in the European Union

Objectives of Directive 2001/20/EC

♦ To provide CAs with overview over all planned and ongoing

trials

♦ To ensure CAs EU-wide supervision of drug safety

♦ To establish EU-wide databases (EudraCT and Clinical

Trials Module of EudraVIGILANCE)
Good Clinical Practice in the European Union

CTD - Related Changes

♦ Need for a EudraCT number for each protocol
♦ Need for study authorization from the health authority

♦ Compilation of an IMPD

♦ Sponsor must be legally established in the EU

♦ Fixed study approval timelines for CAs and ECs

Good Clinical Practice in the European Union

CTD - Related Changes

♦ The overall responsibility of the sponsor for a clinical trial

♦ Requirement for a “qualified person”, responsible for

quality and release of study medication

♦ Competent Authority can suspend the trial

Good Clinical Practice in the European Union

CTD - Related Changes

♦ “Substantial” Amendments need to be approved by CA and
EC
♦ End of study needs to be declared to CA and EC
♦ Summary of the Final Report must be submitted to the CA
and EC within 1 year
♦ New definition: SUSAR (Suspected Unexpected Serious
Adverse Reaction)
♦ Annual Safety Report
Good Clinical Practice in the European Union

CTD - Related Changes

♦ Rules for studies in children and adult patients unable to
give informed consent
♦ RMS are responsible for establishment of EC system and
infrastructure
♦ ECs get authoritative status
♦ Ongoing involvement of EC during the trial
♦ Need for increased professionalism, additional
administrative burden for ECs
Good Clinical Practice in the European Union

CTD – Implementation How?

♦ 1 opinion per RMS but it is up to the RMS how the single
opinion is achieved
♦ Proposal for a standardized application form: Part I
identical with application to the CA, Part II specific to ECs
♦ Applicant according to national requirements
♦ Differences in required documentation in different RMS
even broader than for CAs
♦ Most RMS have coordinating/central and local ECs and
sponsor still has to submit and handle opinion differences
 Good Clinical Practice in the European Union

CTD – Implementation How?

♦ Opinion within 60 days or less,
for IMPs for gene or somatic cell therapy or products
containing genetically modified organs opinion within 90
days,
180 days if external experts need to be consulted,
no time limit for xenogenic cell therapy
♦ 1 x request for additional information possible, clock-stop
♦ EC approves Substantial Amendments within 35 days or less,
receives end of study declaration
and summary of final report
Good Clinical Practice in the European Union

CTD – Safety Reporting Requirements

♦ Notification of life-threatening SUSARs within 7 (+8) days to
EC, CA and investigators

♦ Notification of other SUSARs within 15 days

♦ Annual Safety Report to EC and CA on SAEs,

safety of the subjects and
risk/benefit assessment
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ History:
CTD announced the preparation of Guidelines by the
Commission on GCP principles, on the content of the master
file, archiving, qualifications of inspectors and inspection
procedures and on manufacture and import of
investigational medicinal products
First draft of a GCP Guideline did not achieve agreement
among Member States as a guideline did not have the
required legal weight for the topics to be regulated.
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Purpose:
Protection of trial subjects and avoidance of unnecessary
trials
Ensuring that all involved in clinical trials use the same
standards
Ensuring functioning of ECs, harmonised application
procedure and protection of trial subjects
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Purpose:
GCP requires inspections: definition of minimum standards
for qualification of inspectors and for inspection procedures,
especially on the cooperation between CAs
Implementation of ICH-GCP into European legislation
Introducing the EMEA Scientific Guidelines into European
legislation
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Purpose:
Increasing the scope of defined protection of vulnerable patients
to patients temporarily incapable of giving informed consent, e. g.
in emergency situations
Giving RMS the possibility to define modalities for non-
commercial academic CTs, especially in the area of
manufacturing and importation of authorized medicinal products
and for the documentation to be submitted and archived in the
master file. Certain GCP modalities may also be altered by RMS
but the Commission will provide a guideline on this.
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Principles:
Priority of individual vs. society interests
Proper education and training of personnel involved in trials
Trials must be scientifically sound and guided by ethical principles
Procedures to secure quality of every aspect of a trial
Adequate non-clinical and clinical information on IMP to support
trial
Conduct according to Declaration
of Helsinki 1996
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Principles:
Need for a protocol
Investigators and sponsors to consider all relevant guidance
on commencing and conducting a trial
Data protection and proper handling to allow for accurate
interpretation and verification
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Ethics Committee Requirements:
ECs have obligation to adopt rules set out in the Clinical
Trials Directive
ECs must retain essential documents from a trial for at least
3 years after completion of the trial or longer according to
national requirements
Request for appropriate and efficient communication
systems between ECs and CAs of the Member States
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Sponsor Requirements:
A sponsor may delegate any or all of his trial-related functions to
an individual, a company, an institution or an organisation.
However, he shall remain responsible for ensuring that the
conduct of the trial and the final data generated comply with the
Clinical Trials Directive and this GCP Directive
Investigator and sponsor may be the same person
Good Clinical Practice in the European Union

Directive 2005/28/EC –
GCP Directive
♦ Further Requirements for:
Manufacturing and import authorisation
Trial Masterfile and archiving
Inspectors‘ obligations and qualification
Inspection procedures
 Good Clinical Practice in the European Union

Conclusion
ICH-GCP requirements are fully implemented in Europe for CTs with drugs
through Directives and Guidances presented in
EudraLex – Notice to Applicants – Volume 10
however, not for all other clinical trials, e.g in surgery, radiotherapy, medical
devices, etc.
Thus, these trials are only covered by the
EU Note for Guidance on Good Clinical Practice (CHMP/ICH/135/95),
which came into force on 17 January 1997.