GCP In European Union by Dr Amit Bhatt

Slide 1: 

GCP in the EU

Good Clinical Practice in the European Union : 

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 : 

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 : 

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 : 

Good Clinical Practice in the European Union The 13 Principles of ICH – GCP 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 : 

Good Clinical Practice in the European Union The 13 Principles of ICH – GCP 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. 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. 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 : 

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 : 

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 : 

Good Clinical Practice in the European Union The History 2001 Clinical Trials Directive Detailed Guidance's 2005 GCP Directive

Good Clinical Practice in the European Union : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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.