The EU Clinical Trials Directive

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The EU Clinical Trials Directive

• Mark W Lowdell
• Director of Cellular Therapeutics
• RFUCMS
• University College London

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Which EU regulations affect us?

• Medicinal Products Directive
• 2001/83/EC Currently legally binding
• Tissues Cells Directive
• 2004/23/EC Legal requirement 2006
• Blood Directive
• 2002/98/EC Currently legally binding
• Clinical Trials Directive
• Currently legally binding

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EU Clinical Trials DirectiveTimetable - latest

• Feb 01 Member States signed Directive
• Feb 03 Draft Statutory Instrument (SI)
• Oct 03 EU GMP Directive published
• Mar 04 New COREC Ethics form
• Mar 04 UK adopted ICH principles of GCP
• Mar 04 Revised SI laid before Parliament
• 1 May 04 EU Clinical Trials Directive enforced
• ??? EU GCP Directive expected

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EU Clinical Trials DirectiveClinical Trial
Defined
Any investigation in human subjects, other than
an non-interventional trial, intended- (a) to
discover or verify the clinical, pharmacological
or other pharmacodynamic effects of one or more
medicinal products, or (b) to identify any
adverse reactions to one or more such products,
or (c) to study absorption, distribution,
metabolism and excretion of one or more such
products,  with the object of ascertaining the
safety or efficacy of those products
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EU Clinical Trials DirectiveMedicinal Product
Defined

• Any substance or combination of substances
  presented for treating or preventing disease in
  human beings (see 65/65)
• Any substance or combination of substances which
  may be administered to human beings with a view
  to making medical diagnosis or to restoring,
  correcting or modifying physiological functions
  in human beings is likewise considered a
  medicinal product
• May be human, animal, vegetable or chemical

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A somatic cell therapy product
Somatic living cells of human or animal origin,
the biological characteristics of which have been
substantially altered as a result of their
manipulation to obtain a therapeutic, diagnostic
or preservative effect in humans
through Metabolic, Pharmacologic or Immunologic
means.
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What does that mean in practice?
Dear Dr Lowdell   Thank you for your email dated
1 September 2004.   The eligibility for cellular
products to fall within the remit of the CT
Directive will depend upon how the cells are
processed.  In general they do not constitute
medicinal products.  Simple cell selection and
enhancement do not usually define cellular
materials as medicinal.  We are happy to review
the manufacturing processes envisaged to provide
you with more specific advice.   If you require
further advice please contact Dr Godfrey on 0207
084 2463.   Kind regards Clinical Trial
Helpline MHRA
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If you have a cellular IMP what do you need to do?

• Produce to the standard in the European Guide to
  Good Manufacturing Practice, Annex 1 of
  Commission Directive 2003/94/EC
• Donor screening
• Clean-room conditions
• Grade A for all open procedures
• Continuous monitoring of air quality
• Validation of procedures
• Definition of product difficult (CE-marked
  tests?)
• Dry runs expensive (ethics?)
• JACIE standard Quality System and product
  labelling
• Submit product manual to local regulatory
  authority
• Use CE-marked clinical-grade reagents where
  available
• Describes entire production process and
  in-process QC plus results of all validation
  procedures and reproducibility from dry-runs

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Where do you find guidance and standards for a
TQA System?

• JACIE
• The EU Tissues Cell Directive accepts JACIE
  standards as appropriate for compliance with the
  ADDED proviso of clean-room standards

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EU Clinical Trials Directive Definitions

• Site one trust
• Chief Investigator
• In overall charge of trial for both multisite or
  single site
• Principal Investigator
• In overall charge of a site
• Domain
• E.g. a Strategic Area Health Authority
• Employing Organisation (EO)
• Care Organisation (CO)
• Sponsor

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EU Clinical Trials DirectiveSponsor

• Takes ultimate responsibility for initiation,
  management and (arranging) financing of trial
• Applies for Clinical Trial Authorisation
• Applies for Ethics Approval
• Provides indemnity for non-negligent harm
• Reports and records adverse drug reactions
• Ensures GCP for trial and GMP for IMP(s)
• Undertakes monitoring
• Reports trial termination to MHRA and Ethics

Some activities may be shared with research
partners
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EU Clinical Trials DirectiveModels of Sponsorship
Directive defines sponsor as an individual,
company, institution or organisation which takes
responsibility Assumes that sponsor is single
legal entity

• ? Single sponsor e.g. pharmaceutical company
• ? Chief investigators employer, e.g. UCL or RFH
• ? Partnership of institutions, e.g. university
  trust
• ? Group of co-sponsors, e.g. uni, trust, research
  council
• ? Individual need employers permission

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EU Clinical Trials DirectiveModels of
Sponsorship cont.
Example A CI is Trust employee Sponsor, EO CO
Trust
Example B CI is UCL employee EO UCL and CO
Trust Sponsor is either UCL or UCL/RFH
partnership or UCL/RFH/MRC sponsor group
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EU Clinical Trials DirectiveClinical Trial
Material
All IMPs manufactured in a Licensed facility and
released by a Qualified Person
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EU Clinical Trials DirectiveInformed Consent

• Must be taken before any trial specific screening
• Patient to sign date consent form
• Consent form and Subject Information Sheet (SIS)
  should be kept together
• Patient to have copy of SIS to take home

• For incapacitated adults must have consent from
  
• Personal legal representative or
• Professional representative
• fully trained and unconnected with trial

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EU Clinical Trials DirectivePharmacovigilance

• Investigators report all Serious Adverse Events
  (SAEs) to sponsors immediately
• Followed by detailed written report including
  severity and causality
• Suspected Unexpected Serious Adverse Reactions
  (SUSARs) have to be reported too
• Fatal or life-threatening SUSARs must be reported
  within 7 days

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EU Clinical Trials DirectiveTrial documents

• Ensure source documents trial records are
  accurate, complete, maintained accessible
• Documents will be reviewed in monitoring, audit
  and inspection by MHRA

• Ensure that essential documents are in place
• Signed protocol and amendments
• Ethics approval letter
• Signed agreements between parties
• Signed informed consent forms
• etc.

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EU Clinical Trials Directive New trials require

• Trust authorisation
• Unique EudraCT number
• Register on EudraCT database
• Clinical Trials Authorisation from MHRA
• Ethics authorisation using COREC standard form
• Protocol with any amendments to ICH GCP
• Investigators Brochure
• IMP to be manufactured in IMP licensed facility
  and released by Qualified Person
• Investigational Medicinal Product Dossier (IMPD)

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EU Clinical Trials DirectiveInvestigational
Medicinal Product Dossier

• Marketing Authorisation number
• if using products licensed in UK as described
• Summary of Product Characteristics (SmPC)
• if using products licensed in EU as described
• SmPC plus Simplified IMPD
• for licensed products used outside terms of SmPC
• Full IMPD containing full quality, preclinical
  and clinical data
• for new unlicensed products

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EU Clinical Trials Directive Ethics Applications

• Completed COREC standard application form
• Protocol to ICH GCP and summary
• Investigators Brochure
• Informed Consent Form
• Subject Information Sheet
• Arrangements for recruitment of subjects
• Peer review referees comments
• Ethical assessment by chief investigator
• Provision of indemnity or compensation
• Agreements - sponsor/trial site, etc.

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Summary

• Cellular therapeutic products MAY be considered
  an IMP in some cases.
• Currently each application will need to be
  assessed by MHRA
• Production standards are equivalent to JACIE plus
  Clean-Room requirement
• Need to conduct trial to GCP and monitor all
  pathology tests to GLP

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With many thanks to Vicki Latter , UCL CRN
Operations Director