9th ifapp european conference europe's role in clinical research
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Presence and Future Under the
Clinical Trials Directive
Dr. med. Ingrid Klingmann, FFPM, FBCPM Pharmaplex bvba
Brussels
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Clinical Trials Directive
Numbers of Clinical Trials Registered in EudraCT (1 May 2004 to 1 August 2007)
Distinct CTs – 12.122 composed of
♦ CTAs: 22.697
♦ Type of sponsor: - Commercial: 18.319 (80,7%)- Non-Commercial: 4.470 (19,7%)
♦ Sites- Single sites: 6.412 (28,2%)- Multiple sites: 15.017 (66,2%)
♦ Countries - Multiple Member States: 13.652 (60,1%)- Incl. third country sites: 11.392 (50,2%)
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Clinical Trials Directive
European Commission- EMEA Conference on the Operation of the
Clinical Trials Directive and Perspectives for the Future
London, EMEA, October 3, 2007
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Clinical Trials Directive
What Aspects of the CTD Work Well?
♦ Standardisation of the review processes and documentation
♦ Improving EC review process
♦ Single EC opinion
♦ Clear and consistent approval timelines
♦ Unique identifier of CTs
♦ Triggered local investment in infrastructure and training
♦ Increased awareness and improved GCP compliance
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Clinical Trials Directive
What Aspects of the CTD Work Well?
♦ Definition of SUSARs although.... - no standard for „important medical event“ - no consistent reference for „expectedness“
♦ Reporting timelines: 7/15 days
♦ Electronic reporting using ICH E2B format
♦ Recognition of implementation problems - agreement to work on improvements
♦ Recognition to ensure the safety of patients enrolled in clinical trials
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Clinical Trials Directive: Quo Vadis?
What Aspects of the CTD Work Well?
♦ Acceptance of common IMP Dossier by most competent authorities
♦ Acceptance of common (EudraCT) application form by most competent authorities
♦ Sharing of information between competent authorities (EudraCT) promotes safety of research participants
♦ Legal basis for GCP
♦ IMP batch release by QP (no inspection of GMP site required)
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Clinical Trials Directive
What Does Not Work Well?
1. Definitions
♦ Investigational Medicinal Product:
- Different IMP / Non-IMP definition by MSs- Pre- versus post-registration
♦ Amendments:- Unclear definition of „substantial“ vs „non- substantial“
♦ Interventional vs non-interventional vs diagnostic CTs
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Clinical Trials Directive
What Does Not Work Well?
2. CTA Applications
♦ Lack of harmonisation regarding information to be provided in CTA application across MSs
♦ Lack of transparency in MS requirements
♦ Lack of transparency of CA „true“ approval timelines
♦ Diverging decisions of MS on the same CTA
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Clinical Trials Directive
What Does Not Work Well?
3. EC Review
♦ Lack of harmonisation regarding information to be provided in EC review process across MSs
♦ Lack of transparency in EC requirements
♦ Lack of transparency of EC „true“ approval timelines
♦ Diverging decisions of ECs on the same submission
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Clinical Trials Directive
What Does Not Work Well?
3. EC Review
♦ Lack of clarity between CAs and ECs about review responsibilities
♦ Lack of clarity between lead and local ECs about review responsibilities
♦ Lack of legal framework for research in emergency situations
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Clinical Trials Directive
What Does Not Work Well?
4. Amendments
♦ No consistency across MSs in interpretation of „substantial“
♦ Unclear requirements concerning „approval“ versus „notification“ by CAs and ECs across MSs
♦ Lack of consistency concerning the expected handling of non-substantial amendments
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Clinical Trials Directive
What Does Not Work Well?
5. Sponsor
♦ No co-sponsorship possible in multinational CTs
♦ Legal representative requirement for sponsors from third countries is unnecessary bureaucracy and leads to letter box companies
♦ Confusion about the civil and criminal liability of the legal representative
♦ Different insurance requirements across MSs
♦ No standard contractual conditions between sponsor and investigators available
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Clinical Trials Directive
What Does Not Work Well?
6. IMP
♦ IMP definition- pre- vs post-marketing authorisation- GMP requirement- type of documentation required for different
types of IMPs
♦ Scope of GMP manufacturing licence
♦ Required GMP documentation for third country manufacturing
♦ IMP labelling requirements
♦ Lack of clarity on role and responsibility of QP
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Clinical Trials Directive
What Does Not Work Well?
7. Safety Reporting
♦ SUSAR reporting to CA, variation between countries- Multiple submissions in multinational trials- SUSAR: local, within or outside EEA, IMP, trials, indications,...- Unblinding rules
♦ Annual Safety Report, variation between countries- SAR line listings + summary tables: periodic or cumulative, local or global, by trial or all inclusive,
blinded or unblinded
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Clinical Trials Directive
What Does Not Work Well?
7. Safety Reporting
♦ Electronic submission to EudraVigilance- High duplication rate of case studies - Data quality issues, e.g. no narratives,
inconsistencies- IMP not identified- CROs have to register for each trial- EudraVigilance data can‘t be analysed
♦ ECs get „flooded“ with SUSARs, get their capacity occupied with bureaucracy and have no capacity / know-how / enough information to draw conclusions to protect patients
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
General
♦ The Clinical Trials Directive should be replaced by a Regulation
♦ The new legislation should include medical devices
♦ There should be a legal framework to ensure the CTD objectives in an adequately adapted way
for all type of clinical research, e.g. radiology trials, surgery, non-interventional trials
♦ New legislation should apply risk-driven requirements instead of absolute requirements
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
General
♦ The new legislation should streamline processes and interaction between the different players
♦ The new legislation should provide more transparency, e.g CT registry, central database of national requirements in English, etc.
♦ Facilitation of investigator-initiated-trials without creating two quality standards♦ Non-acceptance of non-commercial trials for
marketing authorisations would „kill“ academic research
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
1. Definitions
♦ Same definition of IMP, Non-IMP, and background treatment in all MS
♦ Same definition of interventional / non-interventional / diagnostic CTs in all MSs
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
2. CTA Applications
♦ Single entry point for CTA submission for multi- national trials through EudraCT portal
♦ Single CTA for multi-national trials through central or mutual-recognition procedure
♦ Transparency in MS requirements, e.g. English webpages
♦ Central webpage at EMEA with complete information on requirements of all countries
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation2. CTA Applications
♦ EMEA helpdesk for info on national requirements
♦ Provision of pan-European training for assessors
♦ Clinical Trials Facilitation Group (CTFG) should be strengthened with the official mandate to harmonise the requirements for clinical trial applications and safety reporting across all
Member States.
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
3. EC Review
♦ Adoption of a single EC opinion per Member State
♦ Clarity on scope of responsibilities of central versus local ECs
♦ One common application form for ECs in Europe
♦ Standardized electronic submissions to ECs
♦ Accreditation system for ECs
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
3. EC Review
♦ Introduction of principles on ethical review in emergency situations into the CTD
♦ Governmental funding of ECs to increase independence, capacity and professionalism
♦ ECs should have access to EudraCT information
♦ ECs should be involved in and informed about site inspections outcome
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation4. Amendments
♦ Agreement amongst Member States on what is to be considered „substantial“
♦ Agreement amongst Member States on handling of substantial amendments: approval for
substantial amendments from CAs and/or ECs, notification-only of substantial amendments, etc.
♦ Clarification of interaction between EC and CAs to avoid the need for substantial amendments
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
5. Sponsor
♦ Agreement amongst MSs on possibility of co-sponsorship in multi-national academic trials
♦ „Authorized representative“ instead of „legal representative“ with civil and criminal liability retained by sponsor
♦ Standard template for sponsor agreements with investigators and institutions
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
6. IMP
♦ Agreement amongst MSs on IMP definition in different settings
♦ Redefining GMP requirements for trials with advanced medicines and uniform GMP
requirements for biotherapy
♦ Identical labelling requirements in all MSs
♦ No separate importation approval after CTA but importation should be covered by CTA
♦ Same role and responsibilites for QPs in all MSs
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Clinical Trials Directive
Creative Suggestions for Improvement of the Current Situation
7. Safety Reporting
♦ Only one reporting entry for SUSARs in Europe
♦ Clear content and reporting rules of SUSARs and ASRs
♦ Better use of the EudraVigilance database for signal detection and safety information
dissemination to involved parties
♦ Work sharing for the SUSARs and ASRs assessments within each MS
♦ No expedited SUSAR reporting to ECs but periodic risk-benefit analysis and emergency info
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Clinical Trials Directive
Conclusions from G. Lalis, DG Entreprise♦ Maintain the principles
- protection of subjects- quality of research- favourable research environment
♦ Need for a quick fix of urgent issues within the existing legal framework
♦ Guidelines don‘t work for harmonisation. Directives set the objectives and get „gold-bladed“ by MSs. But we need to solve multi-national studies, get a mutual recognition or central CTA system, streamline the SUSAR reporting mechanism and improve the analysis of the data - and that might require a Regulation for clinical trials
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Clinical Trials Directive
Conclusions from G. Lalis, DG Entreprise♦ „Special modalities“ for non-commercial trials need
to be fundamentally reviewed under the aspect of different risk levels in different types of CTs – however, no double quality standards but reduced administrative burden for all sponsors
♦ Transparency needs to be increased as public trust and confidence must be improved
♦ Guideline will be released on which information from EudraCT can be made public
♦ If larger regulatory changes are envisaged, process will start with a 2-months public consultation process.