Francis P. Crawley Good Clinical Practice Alliance - Europe &

The Future of GCP and EU Regulations Annual Conference of the Bulgarian Association for Clinical ResearchSophia, Bulgaria14 December 2007 Francis P. Crawley Good Clinical Practice Alliance - Europe& Chairman, GCP Drafting GroupWorld Health Organization fpc@gcpalliance.org 1

‘We want clinical trials in the European Union.’ Thomas Lönngren Executive Director, EMEA 3 October 2007, London Do we?

Challenges • Patients for recruitment (Europe #2) • R&D investment (US #1) • Research sites closing in Europe • Quality in research EU share of global research?

EU Directive 2001/20/EC ‘OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001on the approximation of the laws, regulations and administrative provisions of the Member Statesrelating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use’

Ethics CommitteeArticle 2, Definitions (k) ‘ethics committee’: an independent body in a Member State, consisting of healthcare professionals and nonmedical members, whose responsibility it is to protect the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent;

InvestigatorArticle 2, Definitions (f) ‘investigator’: a doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires. The investigator is responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator;

SponsorArticle 2, Definitions (e) ‘sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial;

Competent AuthorityEU GCP Inspections ‘The verification of compliance with the standards of good clinical practice and the need to subject data, information and documents to inspection in order to confirm that they have been properly generated, recorded and reported are essential in order to justify the involvement of human subjects in clinical trials.’ EU Directive (15)

The Guidance Documents • Detailed Guidelines on the principles of good clinical practice in the conduct in the EU of clinical trials on medicinal products 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 useDetailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities in the European Union, notification of substantial amendments and declaration of the end of a clinical trial • Detailed guidelines on the trial master file and archiving to implement the directive on Clinical Trials on medicinal products for human use • Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use • Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance -Clinical Trial Module) • Detailed guidance on the European clinical trials database (EUDRACT Database)

The Guidance Documents (cont.) • Detailed guidelines on inspection procedures for the verification of GCP compliance to implement the directive on Clinical Trials on medicinal products for human use • 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 to implement the directive on Clinical Trials on medicinal products for human use • Manufacturing and/or Import Authorisation of Investigational Products for Human Use-Contents of the Application • Authorization Referred to in Article 13, Paragraph 1 of Directive 2001/20/EC: Requirements to Obtain Authorization and Requirements to Be Met by the Holder of This Authorization • Draft Proposal for a Commission Directive…/…/EC Amending 91/356/EEC, Laying Down the Principles and Guidelines of Good Manufacturing Practice for Medicinal Products for Human Use • Modifications of Commission Directive 91/356/EEC of 13 June 1991 Laying Down the Principles and Guidelines of Good Manufacturing Practice for Medicinal Products for Human Use (two column informal working document) • Volume 4: Good Manufacturing Practices; Annex 13: Manufacture of Investigational Medicinal Products; November 2001

The UK Clinical Trials Regulation The Medicines for Human Use (Clinical Trials) Regulation 2004(SI 2004/1031)

The Belgian Law on Human Research Wet inzake experimenten op de menselijke persoonLoi relative aux expérimentations sur la personne humainedated 7 May 2004published 18 May 2004effective 1 May 2004

The French Law LOI no 2004-806 du 9 août 2004 relative à la politique de santé publique

Confirming Fears ‘Human guinea pigRaste Khan’ The Sun 15-03-2006TGN 1412 Placebo Group, Paraxel CRO

European Ethics vs. Global EthicsFortune Magazine, 8 August 2005 ‘Nearly 40% of all clinical trails are now conducted in poorer countries such as Russiaand India, where costs are lower and patients more vulnerable. And that’s raising questions about ethics and oversight.’ Exploitation of patients, researchers, governments & GCP by EuropeanCRO companies in Eastern Europe.

The Globalisation of Clinical Trials and of GCP & Ethics ‘The episode is a sign that China’s clinical research is jumping ahead of its system for ethical oversight.’ Nature

Industry’s PerspectiveEuropa Bio & EFPIA ‘The potential benefits of the Directive have not been realised in bringing innovative medicinal products to patients and is therefore not consistent with the Lisbon Agenda.’ Alan Morrison, Amgen UK

Challenges (1) • Lack of consistency across member states regarding the contents of the ‘Clinical Trials Application’ (CTA) • Lack of a consistent definition of an ‘Investigational Medicinal Product (IMP)’ • Lack of clarity and consistency regarding the definition of ‘substantial amendment’ • Lack of consistent GMP requirements for IMPs across member states

Challenges (2) • No mutual recognition procedures between competent authorities • Inconsistent application formats to ethics committees within and across MSs • Inconsistent ethical review approaches • Need for a simplification and harmonisation of EU legislation in pharmaceuticals • The definition of ‘non-interventional’ clinical trials needs clarification • Clinical trials in emergency medicine

Challenges (3) • Definition of SUSARs is not clear • The Eudravigilance Database is not being used or resourced consistently and effectively • A drastic overhaul of the Directive risks creating another extended period of uncertainty in the EU with regard to clinical trials. • We need a recommitment to the implementation of the Directive in a harmonised manner.

Academic Complaints (1) • No clear definition of ‘substantial’ for substantial amendments. • Too much paper. • Safety information collection, reporting and review of safety information is ‘unbelievably and unnecessarily complex for multinational trials’ • ‘too much garbage to too many recipients’ • ‘The problem goes back to ICH GCP put together by members of industry and regulators.’ • Inspections: who pays for inspections.

Extend GCP legislation to all clinical trials for diagnosis, medical devices, herbal and homeopathic remedies. Abolish confidentiality on pharmacological and clinical data utilized for drug approval. Devise a minimal set of rules to be applied by all ethics committee (placebo, equivalence, informed consent, surrogate end-points) Academic Complaints (2) • ‘There should be access to EUDRACT by researchers. There is no reason why it should not be public.’ • ‘One of the phase III trials should be made by an independent organisation.’ • Extend GCP legislation to all clinical trials for diagnosis, medical devices, herbal and homeopathic remedies.

Extend GCP legislation to all clinical trials for diagnosis, medical devices, herbal and homeopathic remedies. Abolish confidentiality on pharmacological and clinical data utilized for drug approval. Devise a minimal set of rules to be applied by all ethics committee (placebo, equivalence, informed consent, surrogate end-points) Academic Complaints (3) • Abolish confidentiality on pharmacological and clinical data utilized for drug approval. • Devise a minimal set of rules to be applied by all ethics committee (placebo, equivalence, informed consent, surrogate end-points) • ‘The Directive is a good example of unanticipated consequences of good intentions.’ • ‘Academic research is poor. There should be an exemption for academic researchers from fees.’

Requests • A revision of the Directive with amendments and a review of MS legislation • The aim should be greater harmonisation, transparency, and consistency in approach across the EU • Standardise electronic submissions to CAs and ECs • Accreditation of ECs and investigators and sites • Clinical trial registry (EUDRACT) with public availability and a results database

The Role of theNational Competent Authorities • Hartmut Krafft – PEI, Germany – Chairman of the Clinical Trials Facilitation Group (CTFG) • 97.1 percent approval of clinical trials by competent authorities in Europe • Discussion (scientific advice meetings) should happen before submission of the application to the CAs. • The CTFG as the place to resolve problems in harmonisation

Fernand SauerHonorary Director General of the European Commission • Evaluate and consolidate provision protecting clinical trial subjects inside and outside the EU, avoiding clinical ‘dumping’ • Receive input from pharmaceutical companies and WHO/TDR involved in clinical trials in poor countries, trial registries public? • Promote adaptation of GCP principles via the WHO • Help develop ethics in developing countries • Support capacity-building in developing countries • Increase support to non-commercial clinical research

Georgette Lalis (1)PharmaceuticalsDG Enterprises European Commission • ‘The Commission wants to see the system run smoothly. By using a Directive we were helping Member States to gold plate their own measures.’ • Some member states abide to what they agree, but the great majority do not. • The Commission is now tending to divert all legislation to regulations. If we decide to change something, we might go down the road of a regulation. • We can take with us all of the improvements suggested without changing the legislative framework.

Georgette Lalis (2)PharmaceuticalsDG Enterprises European Commission • The safety monitoring of clinical trials is an issue. We have a lot of requirements that do not produce efficient results. • We need to check if the specificity of non-commercial trials are being taken into account by the Member States. • We are introducing discussions on clinical trials in all our regular ongoing discussions with countries such as Russia, India, and China. We need to see the frameworks coming together. • ‘I cannot say we can change the legal framework.’

GCPA2 Questions Questions • Following the 3 October 2007 conference, do the European Commission and EMEA believe that Directive 2001/20/EC is a major contributor or detractor to public health in Europe. • Following the 3 October 2007 conference, do the European Commission and the European Medicines Agency (EMEA) believe that Directive 2001/20/EC is a key contributor or detractor in making Europe competitive in the global market place of clinical trials?

GCPAThe Way Forward (1) • A permanent and ongoing clinical trial legal, scientific, and ethics observatory should be established at the European-level for the ongoing review of the implementation of Directive 2001/20/EC into Member State laws, regulations, and administrative provisions to identify variances and provide guidance on corrective measures, as appropriate, and to maintain an ongoing evidence-based system for impact assessment. • The review should be mandated to consider all law, regulation, administrative procedures, standards, and guidance related to clinical trials in Europe.

GCPAThe Way Forward (2) The European Commission should propose to the European Parliament and Council a limited number of amendments to Directive 2001/20/EC. • The following amendments should be submitted for review: • The EUDRACT database should be made publicly accessible for all clinical trials in its totality. EUDRACT should also be brought in conformity with the WHO 20 required items; it should be listed as a WHO Primary Registry; and consultations should be undertaken between EUDRACT and other key clinical trial registries: India, China, South Africa, US.* • A publicly accessible clinical trials results database should be added to EUDRACT or opened parallel to EUDRACT. • A clear definition of ‘investigational medicinal product’ should be added to the Directive.

GCPAThe Way Forward (3) • The term ‘sponsor’ should be redefined as follows: ‘The legal entity responsible for the organisation of a clinical trial.’ • The term ‘investigator’ and its definition should be deleted. • Sponsors should be made fully responsible for SUSAR reporting and SUSAR analysis. . . . SUSARs should only be reported to ethics committees in the form of ‘notifications’ (no actions required). • All distinctions between commercial and non-commercial/academic clinical trials should be eliminated from the Directive. Sources and nature of funding are not GCP considerations. Similarly, distinguishing clinical trials on the basis of risk assessment is inappropriate.

GCPAThe Way Forward (4) • The European Commission Clinical Trials Facilitation Group (CTFG) should draw up a list of areas in which the 27 member states are in agreement and a list of areas in which the 27 member states have differences regarding the implementation of Directive 2001/20/EC. The CTFG should identify which areas of disagreement it will address and provide timelines for addressing these areas of disagreements. These lists and timelines should be made available for public discussion prior to finalisation. • Two representatives of European patient organisations should be invited to participate as observers in the meetings of the European Commission Clinical Trials Facilitation Group (CTFG).

GCPAThe Way Forward (5) • The EMEA should develop a strategic plan for cooperation with Third Countries in clinical trials. This strategic plan should be made a subject of public debate during its development. • The European Commission should engage a global discussion on a revised GCP standard that corrects the inaccuracies and incompleteness of the ICH GCP (1996) as well as updates the guideline based on developments in clinical trials over the past 12 years. This revision process should not be limited to industry and regulatory authorities from the European Union, United States, and Japan. In particular, all regions of the world should be included and patients provided a leading role.

The Establishment ofGlobal GCP Practices Responding to the Challenges The GCPA has assisted to establish: • The Indian Forum for Good Clinical Practice(Mumbai, India; February 2005) • The Forum for Ethical Review Committees in China(Shanghai, China; February 2005) • The Nigerian Association for Good Clinical Practice(Enugu, Nigeria; October 2005) • Central Asian Forum for Ethics and Good Clinical Practice in Health Research Systems(Almaty, Kazakhstan; May 2007) • The Uganda Forum for Research Ethics (Kampala, Uganda; November 2007)

The Need to Revise GCP • The strengths of existing GCP Guidelines and laws • ICH • WHO (1995, 2005) • US CFR • EU Directive 2001/20/EC • South Africa, India, Singapore, and other national GCP Guidelines • The need to achieve a more global guideline • The need to expand the concept of GCP from ‘clinical trials’ to ‘health research’ • The need to include more sets of responsibilities • The need to take into account new developments in clinical/health research

The Revision ProcessA. Recognising the Strengths of Existing GCP Guidelines and Laws • The basic chapters • Ethics committees • Investigators • Sponsors • The glossaries • The introductory texts

The Revision ProcessB1. Including new (required) guidance New Chapters • Government Regulatory Agencies- roles and responsibilities • Regulatory • Advisory • Oversight • Participants (patients, subjects, communities) - roles and responsibilities • Informed • Consulting • Engaged • Role of patient organizations • Role of Community Advisory Boards

The Revision ProcessB2. Including new (required) guidance New Topics • The role and responsibilities of DSMBs/DMCs • The role and responsibilities of Community Advisory Boards • The role and responsibilities of Clinical Trial (Research) Registries • The publication of research results • Data ownership (custodianship) • Deepening the discussion on informed consent, with greater emphasis on the process of informed consent • Vulnerable patient populations • Patient/Subject and Community privacy and confidentiality • Risk Management • Safety Monitoring and Pharmacovigilance

Partnerships for Ethics and Science in Paediatric ResearchGCPA Actions

European Network for Expertise for Rare Paediatric Neurological Disorders nEUroped (European Commission FP7, 2008-2011 funding) Objectives • Establishing a European network of patients and researchers with a common interest in rare paediatric neurological disorders • Establishing a patient and research registry for rare neurological disorders in the European Union

European Network for Expertise for Rare Paediatric Neurological Disorders nEUroped Partners • European Network for Research on Alternating Hemiplegia • University College London • Univerzita Karlova v Praze, 1. lekarska fakulta • Hospices Civils de Lyon • University of Bologna • European Organisation for Rare Diseases • Good Clinical Practice Alliance – Europe • HC Forum • Associazione Italiana per la Sindrome di Emiplegia Alternante Onlus • IRCCS E.MEDEA – Ass.ne La Nostra Famiglia • Leiden University Medical Center (AZL) • Hospital de Sant Joan de Déu • University Medical Centre Ljubljana, Children’s Hospital

European Network for Expertise for Rare Paediatric Neurological Disorders nEUroped Collaborating Partners • European Paediatric Neurological Society (EPNS) • René Descartes Medical School, European Network of Pediatric Research • Orphanet • European Federation of Neurological Associations • Groupe Hospitalier Pitié-Salpêtrièrel • Semmelweis University • Hospital General Universitario, Gregorio Marañón • Centre Pédiatrique des Pathologies du Sommeil, Hôpital Robert Debré • University Hospital Necker-Enfants Malades • University Hospital Gasthuisberg- KU Leuven • Centro per la Chirurgia dell’Epilessia Claudio Munari • Behandlungszenntrum Vogtareuth, Neuropedaitric Clinic • University Medical Centre (UZ Utrecht) • Association Francaise de l´Hémiplégie Alternante • Fonazione Centro San Raffaele del Monte Tabor

Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical TrialsRESPECT(European Commission FP7, 2008-2011 funding) Objectives • to identify the needs of children and their families as related to outcomes in clinical trials • to identify methods by which these needs can be translated into empowering and motivating participants in future clinical trails research

Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical TrialsRESPECT Partners • Universitet Göteborg, Paediatric Clinical Trails Group • University Hospital of Hamburg-Eppendorf, Department of Medical Psychology • European Patients’ Forum • University Children's Hospital Ljubljana And the Foundation of Child Neurology • Good Clinical Practice Alliance – Europe • Azienda Ospedaliera di Padova • Consorzio valutazione Biologiche e Farmacologiche (Pavia)

Partnership for Ethics in Paediatric Research • Good Clinical Practice Alliance – Europe • Working Group on Ethics, Union of European Medical Specialists – European Academy of Paediatrics (UEMS-EAP) [formerly CESP] • Institute of Clinical Research (ICR) • European Network for Alternating Hemiplegia in Childhood (ENRAH)+ nEUroped, RESPECT (from 2008) • European Network of Allergy and Airway Diseases Patients’ Organisations (EFA) • International Primary Care Respiratory Group (IPCRG) European Network for Alternating Hemiplegia in Childhood (ENRAH) (Barcelona, Spain; 9 February 2006)

Partnership Initiatives • EU Operational Guidelines for Informed Consent/Assent in Paediatric Research • EU Operational Guidelines for the Ethical Review of Paediatric Research • EU Education Programmes for Paediatric Investigators and Ethics Committee Members • A European network for GCP in paediatric clinical trials + GCP guidance for paediatrics • A European initiative for international cooperation in paediatric ethics EFA/GA²LENWorkshop for Patient Representatives(London, United Kingdom; 19 April 2007)

What regulatory changes would improve clinical research in Europe? fpc@gcpalliance.org

Francis P. Crawley Good Clinical Practice Alliance - Europe &