9th IFAPP European Conference Europe's Role in Clinical Research

Presence and Future Under the

Clinical Trials Directive

Dr. med. Ingrid Klingmann, FFPM, FBCPM Pharmaplex bvba

Brussels


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%)


European Commission- EMEA Conference on the Operation of the

Clinical Trials Directive and Perspectives for the Future

London, EMEA, October 3, 2007


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



♦ 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

Clinical Trials Directive: Quo Vadis?


♦ 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)


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



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



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



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



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



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



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



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



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


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



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



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



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


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.



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



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


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



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



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



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


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


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.

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9th IFAPP European Conference Europe's Role in Clinical Research