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GCP in the EU

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Good Clinical Practice in the European Union

The History

1946 Code of Nrnberg

1964 Declaration of Helsinki

1979 Belmont Report

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The History

In the Nineties:

EU-GCP Guideline

Nordic Guidelines

ICH-GCP-Guideline

WHO Guidelines

CIOMS Guideline

EU-Note for Guidance on GCP

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The 13 Principles of ICH GCP

1. Clinical trials should be conducted in accordance with theethical 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.

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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

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6. A trial should be conducted in compliance with the protocolthat has received prior institutional review board (IRB) /

independent ethics committee (IEC) approval / favourableopinion.

7. The medical care given to, and medical decisions made onbehalf 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 bequalified by edcuation, training, and

experience to perform his or her task(s).

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9. Freely given informed consent should be obtained from

every subject prior to clinical participation.

10. All clinical trial information should be recorded, handled andstored in a way that allows its accurate reporting,interpretation, and verification.

11. The confidentiality of records that could identify subjectsshould be protected, respecting the privacy andconfidentiality rules in accordance with the applicableregulatory requirements.

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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.

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The History

2001 Clinical Trials Directive

2002 Detailed Guidance's

2005 GCP Directive

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The New Regulatory Environment forClinical Trials

Directive 2001/20/EC (Clinical Trials Directive) hascome 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) releasedOct 8, 2003

Directive 2005/28/EC (GCP Directive)

released April 8, 2005

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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

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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)

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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)

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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)

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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

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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

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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 AdverseReaction)

Annual Safety Report

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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 administrativeburden for ECs

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CTD Implementation How?

1 opinion per RMS but it is up to the RMS how the singleopinion is achieved

Proposal for a standardized application form: Part I identicalwith application to the CA, Part II specific to ECs

Applicant according to national requirements

Differences in required documentation in different RMS evenbroader than for CAs

Most RMS have coordinating/central and local ECs andsponsor still has to submit and handle opinion differences

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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

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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

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Directive 2005/28/EC GCP Directive

History:

CTD announced the preparation of Guidelines by theCommission on GCP principles, on the content of the masterfile, archiving, qualifications of inspectors and inspectionprocedures and on manufacture and import of investigationalmedicinal products

First draft of a GCP Guideline did not achieve agreementamong Member States as a guideline did not have therequired legal weight for the topics to be regulated.

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Directive 2005/28/EC

GCP Directive

Purpose:

Protection of trial subjects and avoidance of unnecessarytrials

Ensuring that all involved in clinical trials use the same

standardsEnsuring functioning of ECs, harmonised applicationprocedure and protection of trial subjects

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Purpose:

GCP requires inspections: definition of minimum standardsfor 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 Europeanlegislation

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Purpose:

Increasing the scope of defined protection of vulnerable patients topatients temporarily incapable of giving informed consent, e. g. inemergency situations

Giving RMS the possibility to define modalities for non-commercialacademic CTs, especially in the area of manufacturing andimportation of authorized medicinal products and for thedocumentation to be submitted and archived in the master file.Certain GCP modalities may also be altered by RMS but theCommission will provide a guideline on this.

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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 supporttrial

Conduct according to Declaration

of Helsinki 1996

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Principles:Need for a protocol

Investigators and sponsors to consider all relevant guidanceon commencing and conducting a trial

Data protection and proper handling to allow for accurateinterpretation and verification

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Ethics Committee Requirements:

ECs have obligation to adopt rules set out in the Clinical TrialsDirective

ECs must retain essential documents from a trial for at least 3years after completion of the trial or longer according tonational requirements

Request for appropriate and efficient communication systemsbetween ECs and CAs of the Member States

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GCP Directive

Sponsor Requirements:

A sponsor may delegate any or all of his trial-related functions toan individual, a company, an institution or an organisation.

However, he shall remain responsible for ensuring that the conductof the trial and the final data generated comply with the ClinicalTrials Directive and this GCP Directive

Investigator and sponsor may be the same person

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Further Requirements for:

Manufacturing and import authorisation

Trial Masterfile and archiving

Inspectors obligations and qualification

Inspection procedures

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Conclusion

ICH-GCP requirements are fully implemented in Europe for CTs with drugs throughDirectives and Guidances presented in

EudraLex Notice to Applicants Volume 10

however, not for all other clinical trials, e.g in surgery, radiotherapy, medicaldevices, 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.

Documents

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