EORTC

EU Clinical Trials Directives

Organisation and Implementation of Cancer Clinical Trials

Anastassia Negrouk

EORTC Regulatory Affairs Manager

Intergroup Officer

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Contents

Introduction

Scope

Definitions

Main Issues

Impact

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Introduction (1)

Full TitleDirective 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 States relating to the implementation of good clinical practice

in the conduct of clinical trials on medicinal products for human use.

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Introduction (2)

Directive means it is directed towards the Member States, obliging the member states to achieve the result,

but

they remain free to choose the forms and methods to achieve that result

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Introduction (3)

Time Lines

Released 4 April 2001

To be Adopted and published before 1 May 2003

To be Applied on 1st of May 2004 at latest

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Status of Implementation into National Legislation

Effective from 1st May or before Austria Belgium Czech Republic Denmark Hungary Ireland Italy Latvia Lithuania Poland Slovakia* Spain Sweden UK

Late implementation Estonia Cyprus Finland Germany Greece Portugal Malta Slovenia Luxemburg

Implemented, but not applicable yet The Netherlands (01/03/2006)

Not yet fully implemented France (decree awaited)

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Scope

The Directive establishes specific provisions regarding the conduct of clinical trials, including multi-centre trials.

Does not apply to non-interventional trials

Detailed guidelines published by the commission

All clinical trials shall be designed, conducted and reported in accordance with the principles of good clinical practice

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Definitions

‘clinical trial’: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more IMP(s) and/or to study absorption, distribution, metabolism and excretion of one or more IMP(s) with the object of ascertaining its (their) safety and/or efficacy;

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Definitions

‘non-interventional trial’: a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study…..

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Definitions

‘investigational medicinal product’: a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or used for an unauthorised indication, or when used to gain further information about the authorised form;

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Definitions

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

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Main Issues of Directive 2001/20/EC

Protection of trial subjects

Opinion of the Ethics Committee

Authorisation by Competent Authority

Conduct

European Database (EUDRACT)

Suspension of the trial

Manufacture, import and labelling of IMPs

Inspections

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Protection of clinical trial subjects

The foreseeable risks and inconveniences have been weighed against the anticipated benefit ………

Trial subject (or legal representative) has had the opportunity to understand the objectives, risks and inconveniences …….

Written consent

Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor

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Minors and incapacitated adults

Those incapable of giving consent must be protected Informed consent of the parents or legal representative The minor or person not able to give informed legal

consent has received info according to its capacity of understanding

The explicit wish of a minor …… is considered

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Ethics Committee - timelines

60 days maximum from receipt of a valid application May send a single request for supplementary information Clock stops until receipt of the supplementary information No extension to 60 day period except in case of

Gene therapy Somatic cell therapy Medicinal products containing genetically modified organisms 30 day extension, plus further 90 days if consultation with group or

committee

No time limit for xenogenic cell therapy

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Ethics Committee - application

The Ethics Committee shall give its opinion before a trial commences, considering:

Relevance and design Risks and benefits Protocol Suitability of investigator and supporting staff IB Quality of facilities PIS / IC documentation and process Provision for indemnity or compensation in the event of injury or death

attributable to a clinical trial Insurance or indemnity to cover the liability of the investigator and sponsor Rewards / compensation to investigators / trial subjects Relevant aspects of any agreement between sponsor and site Arrangements for recruitment

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Competent Authority

Sponsor may not start until Ethics Committee has issued favourable opinion CA concerned has not informed the sponsor of any

grounds for non-acceptance

Can run in parallel, or not

60 days maximum from receipt of a valid application 30 day extension as for Ethics Committee

If CA does not accept, sponsor may amend request ONLY ONCE

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Competent Authority - application

Covering letter Clinical Trial Application Form Protocol IB IMPD

Full IMPD if: No previous applications for the product and cannot cross refer to info

submitted by another sponsor Simplified IMPD if:

If info previously assessed as part of a Marketing Authorisation in any MS in the Community

If within the SPC – SPC is sufficient If outside SPC – SPC plus non-clinical data, clinical data

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Conduct of a clinical trial

Amendments may be made If deemed substantial an approval is required Sponsor will notify

MSCA concerned Ethics Committees concerned

EC to give an opinion within 35 days If favourable and CA raised no objection, amendment may be

implemented If unfavourable, cannot be implemented

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Conduct of a clinical trial

The sponsor and investigator shall take appropriate urgent safety measures to protect subjects against immediate hazard

Sponsor has 90 days to notify CA and EC of end of a trial

15 days if trial is terminated early

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European Database

Member States shall enter info into a European database: Extracts of the request for authorisation Any amendments to the request Any amendments to the protocol The favourable opinion of the EC A reference to any inspections carried out

Only accessible to MSCA, EMEA and the European Commission

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Suspension of the trial or infringements

MSCA may suspend or prohibit the clinical trial, and shall notify the sponsor, for reasons of safety, scientific validity, if conditions of request are no longer met

Will ask the sponsor and/or investigator for opinion

MS CA shall inform the other CAs, the EC, the Agency (EMEA) and the Commission of its decision

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Investigational Medicinal Products

Manufacture and import is subject to authorisation

To obtain the authorisation, the applicant shall meet the requirements: At least one qualified person who ensures

GMP If manufactured in a third country, GMP standards Comparator from a third country with no GMP equivalent documentation,

retesting to confirm the GMP status

IMPs (and the devices used for their administration) shall be made available free of charge by the sponsor unless MSs have established precise conditions for exceptional circumstances

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Labelling of IMPs

At least the official language(s) of the MS on outer packaging, or when no outer packaging, on the immediate packaging

Guidelines – GMP Annex 13

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Inspections

MS shall appoint inspectors to verify compliance Trial sites Manufacturing site Labs used for analysis Sponsor’s premises

MS shall inform the Agency

Results recognised by the other MSs

Inspections coordinated by the Agency

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Impact

Differences between member states

Increased administrative requirements

Increased manpower

Increased cost All of the above, plus Fees for CA applications Fees for CA amendments Fees for Ethics Committees

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Concerns for multinational non commercial trials

Sponsorship

Definition of IMP and related provisions

Pharmacovigilance

Increased Costs

Amendments

Contractual Issues

Lack of Communication and Harmonisation

Free access to IMPs

Clinical trial insurance

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IMP supply

“Unless Member States have established precise conditions for exceptional circumstances,

investigational medicinal products and, as the case may be, the devices used for their administration

shall be made available free of charge by the sponsor”

Article 19, Directive 2001/20/EC

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Ethics Committees

Confusion and lack of coordination Who makes the submission? Timelines for approval unclear/coordination between the Central/Local EC unclear

Does the single opinion really exist? Language Barriers Supporting texts for National legislations not available / not

user friendly Administrative Requirements Belgium: 18 copies Luxembourg: 13 copies Austria: 21 copies Estonia: 11 copies

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Competent Authorities Administrative Issues Level of information increase Quantity of information increase (France: 8 Copies, U.K.: 6 copies) Additional requirements not mentioned in the Guidance documents

Language Barriers (Spain, Poland) Lacking Information for some Member States

Cyprus, Malta

Additional National Requirements National application forms (Ireland, Poland) National databases (Italy Osservatorio)

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Clinical Trial Insurance Huge variability per country in term of

Compensation Juridical background Duration of compensation Exclusion Costs

Major misunderstanding by ECs leading to delays, variability within countries

Urgent need to initiate a European forum to address this critical issue.

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Insurance costs related to patients in EORTC clinical trials (in euros)

€40€50€60€70€80€90€100€110€120€130€140

1996 2000 2002 2005

Thousands

Cost/year

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Current Challenges

Clinical Trials Directive 2001/20/EC Increase in trial costs Increase in complexity

EORTC Standard Operating Procedures (SOPs) Adapt to changing regulatory environment Impact on

Regulatory Affairs Unit / Safety Desk Statistics Department IT Unit Coordinating Physicians

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Future Challenges

Communication Competent Authorities Ethics Committees Academic partners Commercial partners

Harmonisation of Ethics Committee procedures

Meeting the increased costs

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European Legislation

GCP DIRECTIVE 2005/28/EC 8th April 2005 Released Details :

the principles of GCP referred to in Directive 2001/20/EC the requirements for the authorisation of the manufacture

or importation of IMPs as foreseen in Directive 2001/20/EC; guidelines on the documentation relating to clinical trials,

archiving , qualifications of inspectors and inspection procedures in accordance with Directive 2001/20/EC

to be implemented in all Member States by January 29th 2006

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Questions?