Impact of the transposition of the European Clinical Trials Directive CEMO, Paris 17 November 2004 Dr Martine Dehlinger-Kremer VP Regulatory Affairs International
Agenda Overview of key areas of Directive 2001/20/EC Applications to EC and CA Safety Reporting Investigational Medicinal Product Current implementation in France Current implementation in EU Member States
Overview of Key Areas Scope Implementation of good clinical practice for all clinical trials in Europe including bioavailability and bioequivalence studies Do not apply to non-interventional studies Timelines Adopted 4 th April 2001 / Published in OJ 1 st May 2001 Member States to implement Directive into national law until 1 st May 2003 1 st May 2004 Provision to be applied
Directive 2001/20/EC Overview of Key Areas 25 Member States of European Union 15 old Member States Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden, United Kingdom 10 new Countries which joined the EU on 1 st May 2004: Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovak Republic, Slovenia Norway, Iceland and Liechtenstein Since 01 January 2000 for Registration Procedures Total: 25 EU Countries + Iceland, Norway and Liechtenstein
Overview of Key Areas Pharmacogivilance (SAE Reporting) General Provisions Scope Manufacture and Import of IMP S Labelling Verification of GCP & GMP Commencement of a Clinical Trial Conduct of a Clinical Trial (Amendments) Exchange of Information Clinical Trials Directive Ethics Committee Single Opinion Definitions Protection of Clinical Trial Subjects Clinical Trials on incapacitated adults not able to give informed consent Clinical Trials on Minors Suspension/ End of a Trial
Directive 2001/20/EC Application to Ethic Committee Ethics Committee : One country - One vote Opinion within 60 days Single request issued within the examination period Drugs for gene therapy, somatic cellular therapy & products with GMOs: The 60 days period can be extended for 30 days The 90 days may be extended for another 90 days (180 days) in case expert committee is consulted Drugs for xenogenic cellular therapy: Authorisation period not limited EC review: Sequentially or in parallel with CA review (choice of the applicant) Applicant: sponsor, legal representative, PI
Application to Competent Authorities Commencement of a Clinical Trial If no objection: Start within 60 days of valid application. MS may shorten evaluation time Drugs for gene therapy, somatic cellular therapy and products with GMOs: + 30 days Written authorisation may be required: biotech medicinal products, biological products of human or animal origin, products containing biological components or manufactured with biological components Written authorisation mandatory: medicinal products for gene therapy, somatic & xenogenic cellular therapy and products with GMOs
Application to Competent Authorities Commencement of a Clinical Trial Sponsor or Legal Representative in Community to submit request for authorisation Copy of EC opinions if available Check language of submission with CA EudraCT number A contact person per Member State
Application to Competent Authorities Investigational Medicinal Product Dossier (IMPD) IMPD to be presented in CTD format Full IMPD Quality data + critical analysis of data + assessment of safety of product Summaries of all previous studies Overall risk and benefit assessment (Critical analysis of risk/benefit) Simplified IMPD IMP assessed previously as part of MA in any MS or as CTA to the CA concerned Discussion on potential risks/benefits of proposed trial to include For marketed product when within conditions of SPC approved Comparative trials
Application to Competent Authorities Data for Application to CA Data to be submitted to CA are not fully harmonised throughout all countries Table in Guideline with the different requirements per country
Application to EC and CA Conduct of a Clinical Trial Amendments To be submitted to competent authority of MS and EC EC: 35 days for opinion If favourable opinion of EC and no objections of CA the study may proceed according to amendment
Application to EC and CA Suspension, End of a Clinical Trial Trial stopped prematurely: EC & CA to be informed within 15 days Specific form to be completed Completion as planned: CA & EC to be informed within 90 days Summary of trial report to be submitted within one year of end of the trial to EC & CA (format to comply with ICH E3)
SUSARS Report to Directive 2001/20/EC Safety Reporting Competent Authorities and Ethic Committees concerned Member States may take measures to permit that the ECs concerned may only receive expedited individual reports of SUSAR occurred in subjects recruited in that MS, provided All SUSARs from MSs and where applicable, 3rd countries are reported at least quarterly (a line listing accompanied by a brief report highlighting the main points for concern; copy to CA) Any changes increasing the risk to subjects and any new issues that may affect adversely the safety of the subjects or the conduct of the trial should be provided asap, but not later that 15 days.
SUSARS Report to Investigator Sites Safety Reporting If appropriate: information aggregated in a line listing of SUSARs in periods warranted by the nature of the clinical development project and the volume of SUSARs generated Concise summary of the evolving safety profile added to the line listing If significant safety issue identified (receipt of an individual case report or review of aggregate data) sponsor to issue asap a communication to all investigators
Safety Reporting Format of SUSAR Reports Electronic reporting (expedited reporting to CA) Format & content Eudravigilance Guidance CIOMS-I: accepted standard SUSARs should be identified by A unique clinical trial identification (Eudract number, or in case of non-eu trials the sponsor s trial protocol code) A unique case identification: case identification number in the sponsor s safety database
Directive 2001/20/EC Eudravigilance database Safety Reporting Established & maintained by EMEA SUSARs entered into CT module of Eudravigilance database Required for : Overview of SUSAR occurrence in all clinical trials in Community Facilitation of communication between CAs, Commission & EMEA Separate review of SUSARs occurring in a single MS Generation of signals concerning safety of IMPs Through it's interface with Eudract database, review of safety data in particular populations groups of products therapeutic areas/ pathology/ indication trials conducted by a given sponsor
Annual Safety Reports Safety Reporting Once a year throughout clinical trial or upon request by a CA Several clinical trials conducted with the same IMP: Report to include a Global Analysis of the safety profile based on ALL clinical trials The reporting period starts with the date of the first authorisation for one of these trials by the CA in any Member State and ends after the close of the last trial in any MS
Investigational Medicinal Product Manufacturing Manufacturing of IMP to be GMP compliant (manufactured in accordance with Directive 2003/94/EC) Labelling of Investigational Medicinal Product Annex13 of Directive 2003/94/EC Manufacturers, Importer subject to an authorisation (application!) GMP inspections Audit of manufacturing sites and testing site by MS
Investigational Medicinal Product Qualified Person At least one QP for GMP compliance and batch release Each batch manufactured and checked according to EU-GMP In case of import, QP at manufacturing site and at importer site For comparator: either documentation on GMP or complete re-testing
Current Implementation in France Directive not in force yet Pilot Phase for start of phase 1 studies since Nov. 2003 Pilot Phase for phase 1, 2, 3, 4 studies since 01 May 2004 Start of trial now 3 options 1. Under current Law, i.e. Loi Huriet 2. Acccording to Pilot Phase 3. Under Law Huriet and Pharmacovigilance according to Directive 2001/20/EC After implementation of Directive: transition period for studies running under Law Huriet after which all trials have to comply with Directive
Current Implementation in France Start dates for AFSSAPS evaluation are fixed Start on Monday (15 Nov, 22 Nov, etc.) Dossier to be submitted Friday prior Monday Paper submission before 12 a.m. Electronic submission 8 a.m. Evaluation time phase 1 study phase 2, 3 study simplified dossier, phase 4 14 days. If questions: 30 days 30 days. If questions: 60 days 14 days During pilot phase, opinion of AFSSAPS not mandatory to start study ( demande d évaluation )
Current Implementation in France Biological products, biologicals used in production: viral safety report to AFSSAPS before CCPPRB Products for gene therapy, somatic & xenogenic cellular therapy and products with GMOs: Viral Safety and AFSSAPS approval Already under Law Huriet - only new format
Current Implementation in France AFSSAPS to be informed on study start (first IC signed in France) Amendment to be submitted at fixed dates unless urgency Study report within 1 year of study end (Annex 1 of ICH note on Clinical study reports) Electronic reporting preferred
Current Implementation in France Major impacts in France Procedure Authorisation of studies & amendments vs notification SUSARs reporting to EC Declaration of study end and final report Logistic Preparation of dossiers Eudract database / Pharmacovigilance CT Module database and electronic submissions GCP and GMP for all clinical studies
Current Implementation in the EU Not fully implemented in all EU Member States Current situation National transposition: no consistent process, no timing Amendments for ongoing studies: no harmonised approach Ethic Committees procedure and single opinion: different procedures in Member States
Benefits First step to more harmonisation in area of clinical trials in EU better harmonisation of application formats for EC and CA Quality IMP: Draft CHMP/EMEA Guideline planned for Nov. 04 Shorter time frame for early development in phase I studies Heads of Agencies have set up a Clinical Trials Coordination Group Possibility for a mutual recognition of CT applications in future? For MA faster approval procedure with less problems because CA knows the product already?
Thank you! Omnicare Clinical Research understands what it takes to develop and market new drugs. phase of development
List of implementing texts Detailed guideline on the principles of GCP in the conduct in the EU of clinical trials on medicinal product for human use Detailed guidance on the application format and documentation to be submitted in an application for an ethics committee opinion on a clinical trial on a medicinal product for human use Detailed guidance on the submission to competent authorities of a request for authorisation of a clinical trial on a medicinal product for human use Detailed guidance on the European clinical trials database (EUDRACT) Detailed guidance on the database of Suspected Unexpected Serious Adverse Reactions Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use Detailed guidelines on the trial master file and archiving Detailed guidelines on the qualifications of inspectors who should verify compliance in clinical trials with the provisions of good clinical practice for an investigational medicinal product Detailed guidelines on inspection procedures for the verification of GCP compliance Detailed guidelines on inspection procedures for the verification of GMP compliance Detailed guidelines on the Community basic format and the contents of the application for a manufacturing and/or import authorisation of an investigational medicinal product for human use Commission Directive on the requirements to obtain an authorisation to manufacture or import an investigational medicinal product and the requirements to be met by the holder of this authorisation Revised Annex 13 Manufacture of investigational medicinal products, Volume 4 of the rules governing medicinal products in the European Union Commission Directive 2003/94/EEC as amended
Glossary ADR Adverse Drug Reaction CA Competent Authority EC Ethics Committee EU European Union EMEA European Medicines Agency GCP Good Clinical Practice GMO Genetically Modified Organism GMP Good Manufacturing Practice IMPD Investigational medicinal product dossier MAA Marketing Authorization Application MS Member State SAE Serious Adverse Event SUSAR Suspected unexpected serious adverse reaction