The EU Clinical Trial Directive Implementation : The Realistic Approach in the Netherlands

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The EU Clinical Trial Directive Implementation
The Realistic Approach in the Netherlands
H.D. Veldhuis, Ph.D. Pharma Bio-Research Group
BV PO Box 200 9470AE Zuidlaren, The Netherlands
dveldhuis_at_pbr.nl
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Contents

• EU Clinical Trials Directive (EU-CTD)
• Implementation of EU CTD in Dutch law
• Conclusions

January 2004
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• EU Clinical Trials Directive (2001/20/EC)
• Directive of the European Parliament and of the
  Council on the approximationof the laws,
  regulations and administrative provisions of the
  Member States relatingto implementation of good
  clinical practice in the conduct of clinical
  trials onmedicinal products for human use
• Agreement on Directive reached in February 2001
• Final text published May 1st 2003
• Local (Member State) legislation to be drawn up
  May 1st, 2003
• Application of the local law May 1st 2004

EU Clinical Trial Directive Introduction
January 2004
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• Scope
• conduct within the EU of clinical trials on
  medicinal products involving human subjects
• Some aspects
• sets standards for protecting clinical trial
  subjects, including incapacitated adults and
  minors
• requires Member States to establish ethics
  committees on a legal basis and imposes legal
  obligations in relation to certain procedures,
  such as times within which an opinion must be
  given
• covers certain Licensing Authority procedures
  for commencing a clinical trial
• lays down standards for manufacture, import and
  labelling of IMPs
• requires Member States to set up inspection
  systems for GMP and GCP
• provides for safety monitoring of patients in
  trials, and sets out procedures for reporting
  and recording adverse drug reactions and events

EU Clinical Trial Directive Introduction
January 2004
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• Implementation of EU Clinical Trials Directive
  (2001/20/EC)
• Transposed into Dutch law at December 16, 2003
• To be implemented May 1st, 2004 (National
  legislation in force and to be complied with)
• Working Party IMPD is preparing proposals for
  expertise requirements as well as training
  for certain Independent Ethical Committee (IEC)
  members ( i.e. hospital pharmacists and
  clinical pharmacologists)
• In the Netherlands the previously adapted law
  (1999) already included most of therequirements
  as described in the EU-CTD.

EU Clinical Trial Directive Implementation
January 2004
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• Prior to the start of clinical drug research
  involving humans
• Approval required by two different entities
• - IEC (Independent Ethical Committee METC)
• - CCMO (Central Committee for Research
  involving Human Beings)
  part of the Ministry of Health
• Dossiers for both entities should be identical

EU Clinical Trial Directive Implementation
January 2004
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• Evaluation of the dossier
• METC (Independent Ethical Committee)
• critical evaluation of the research proposal and
  the product
• CCMO ( Competent Authority, CA)
• evaluation of the possible presence of adverse
  events with unacceptable risks in the
  EudraVigilance Database
• marginal evaluation of GCP (focused on
  investigator qualifications)
• Major evaluation of the research proposal by IEC
  marginal evaluation by CA

EU Clinical Trial Directive Implementation
January 2004
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• Evaluation of the dossier
• evaluation by IEC and CCMO in parallel
• evaluation IEC within 60 days (dependent upon
  IEC)
• evaluation CCMO within 21 days (Phase I) or 49
  days (other phases) IEC review period
  within the Netherlands varies from 10 60 days
• Maximum periods (21 and 49 days) implemented
  in law (versus EU-CTD 60 days)
• CCMO intends to provide approval timings
  according to timings of the local IEC

EU Clinical Trial Directive Implementation
January 2004
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• Content of the dossier (major Headings)
• Covering letter
• Eudract number (proof of receipt)
• Application Form (according to EU guidance)
• Clinical Trial Protocol, including
• Informed Consent Form
• Patient Information Leaflet
• Advertisement texts (if applicable)
• Investigational Medicinal Product Dossier
• Signature page
• Investigators Brochure (IB)
• IMPD addendum and related documents
• Amendments, only if substantial

EU Clinical Trial Directive Implementation
January 2004
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• Content of the dossier (details)
• List of decisions of other Competent Authorities
  within EU
• Listing of trials with same product
• Example of Dutch label
• CVs of all investigators
• GCP statement
• Information on facilities
• Insurance volunteers
• Payments to volunteers and investigators

EU Clinical Trial Directive Implementation
January 2004
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Investigational Medicinal Product Dossier (IMPD)

Directive 4.1.6 The IMPD should give
information on quality of any IMP including
reference productsand placebos to be used in the
clinical trial and data from non-clinical studies
and itsclinical use or justify in the
application why information is not provided

• For registered drugs most recent SmPC (product
  labelling) generally sufficient
• For investigational products complete
  information to be provided

EU Clinical Trial Directive Implementation
January 2004
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Investigational Medicinal Product Dossier (IMPD)

• IDB for pre-clinical and clinical information
• Chemical-pharmaceutical information tabulated
  with a minimum of text
• The dossier is not a large document
• The format of the Common Technical Document
  could be used
• Format is not obligatory
• Depending on development phase only limited info
  can be provided
• Dossier dependent upon various factors (Type
  product indication, phase, etc)
• If no data can be provided, an explanation
  should be given
• Certain products (e.g. vaccines, antibodies,
  gene therapy) will be covered by other EU
  guidelines

EU Clinical Trial Directive Implementation
January 2004
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• Investigational Medicinal Product Dossier (IMPD)
• Recommendations for the Netherlands (by the
  Competent Authority)
• IB with addendum on chemical-pharmaceutical
  information is suggested
• Contents not yet made explicit investigator
  should liaise with IEC to discuss and
• agree on format and content
• Additional information should be limited

• Consequences for IECs
• IECs will continue to review the IDB (incl.
  chemical-pharmaceutical information)
• Additional training to be offered for hospital
  pharmacists and clinical pharmacologists
• Consultation possibilities at certain
  governmental research institutes (RIVM, CBG)

EU Clinical Trial Directive Implementation
January 2004
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Confidentiality of Independent Ethics Committees
(IECs)
the Dutch approach requires a number of
studies to be evaluated by the CCMO . All other
studies are evaluated by a local ethics
committee. All ethicscommittees in the
Netherlands are governmental bodies by law and
have to beseen as agencies of the central
committee. They are therefore equally bound
tothe requirements of confidentiality and
independence that apply to any other State body
Excerpt from the 1st Newsletter of the Dutch EU
directive Implementation Working Party
(EUDIWP) December 2003
EU Clinical Trial Directive Implementation
January 2004
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Timing of introduction of the EU CTD in the
Netherlands
There will be no transition period for the
implementation. This means that any trial
submitted before May 1st will not require any
modification to comply withthe new law
Excerpt from the 1st Newsletter of the Dutch EU
directive Implementation Working Party
(EUDIWP) December 2003
EU Clinical Trial Directive Implementation
January 2004
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Amendments

• Substantial amendments
• to be provided to CCMO and IEC
• CCMO notification only
• IEC review and approval according to current
  process
• Administrative amendments
• To be added to own dossier
• Not required to be provided to CCMO and/or IEC
  (only advised)

EU Clinical Trial Directive Implementation
January 2004
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Implication of GMP requirements

• Each batch of study medication to be released by
  a Qualified Person (QP)
• QP to confirm that trial medication has been
  produced according to GMP
• Study medication produced outside the EU has to
  be released by QP in one of the EU Member
  States
• Changes for process of obtaining import licenses
  
• import license will be valid for a
  manufacturing site
• license will cover all trials no need for
  individual requests for every trial

EU Clinical Trial Directive Implementation
January 2004
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• Study termination reporting procedures to CCMO
  and IEC
• For normal completion 90 days
• In case of early termination 15 days
• Final study report (format SYNOPSIS ICH-E3)
  to be submitted within 12 months after study
  completion

EU Clinical Trial Directive Implementation
January 2004
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• GMP and GCP Inspections
• Required under the EU-CTD directive
• Already in place for several years in the
  Netherlands

EU Clinical Trial Directive Implementation
January 2004
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• Event reporting (Eudravigilance)
• Relevant Suspected Unexpected Serious Adverse
  Reactions (SUSARs)
• Sponsor reports to CCMO, IEC
• Fatal or life-threatening SUSARs within 7 days
  ( follow-up in 8 days)
• Other SUSARs asap, but within 15 days
• Annual safety reports (for every study) to CCMO
  and IEC
• to be submitted within 60 days of data lock point

EU Clinical Trial Directive Implementation
January 2004
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Conclusions

• Most EU-CTD requirements have already been in
  place in the Netherlands since 1999
• No changes in timing of a CTA approval for Phase
  I studies
• Only a limited, if any, increase in the CTA
  approval timing for Phase II studies
• (IEC approval timing will be the target for
  the CCMO as well)
• IMPD limited chemical-pharmaceutical
  information to be added to IB
  (requirements to be agreed between IEC and
  CRO/investigator)
• Competitive advantage for CROs with a
  Manufacturing license (GMP) and a QP
• Most additional obligations, required under the
  EU-CTD can be provided by the CRO/investigator

EU Clinical Trial Directive Conclusions
January 2004
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USA Contact

• George Debski
• 860-684-5244
• gdebski_at_pbr.nl