Applied Clinical Trials European Summit

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THE CHANGING NATURE OF ETHICAL REVIEW Prof.
JanHasker G. Jonkman, Ph.D., F.C.P., F.R.Q.A.,
R.Ph., Clinical Pharmacologist University of
Groningen (NL) Professor Quality Management in
Drug Research and Manufacturing and
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CLINICAL RESEARCH (1)

• The Netherlands has a high reputation in clinical
  research
• An international comparison of performance
  indicators for clinical drug trials based on a
  bibliometric study for the period 2001-2004
  indicates
• The Netherlands on place 7 (worldwide)
• The Netherlands on place 4, when total population
  of the country was taken into account

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CLINICAL RESEARCH (2)
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CLINICAL RESEARCH (3)
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CLINICAL RESEARCH (4)

• The high quality of clinical (drug) research was
  also reflected by positive circumstances that
  significantly contributed to it
• international guidelines (a.o. European
  Directives) implemented quickly (sometimes in
  national laws)
• establishment of national guidelines / manuals
• establishment of national laws
• establishment of Good Clinical Practice
  Inspectorate (1993)
• establishment of Medical Ethics Committees in the
  eighties

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CLINICAL RESEARCH (5)

• Example of research guideline
• Guideline for Good Clinical Practice (120 pages)
  September 1993 (revised several times up to
  2003)
• established in cooperation of 11 medical and
  pharmaceutical professional associations and
  pharmaceutical industry
• distributed to all physicians in The Netherlands
• distributed to all pharmacists in The Netherlands

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HISTORY / LEGISLATION OF GCP (1)

• 1994 (official May 02 effective August 01)
• Note for Guidance Good Clinical Practice for
  Trials on
• Medicinal Products in the European Community
• incorporated in law
• (amendment to Article 55 of the Declaration on
  the
• Preparation and Supply of Pharmaceutical
  Products of
• the Law on Drug Supply Besluit bereiding en
  aflevering
• van farmaceutische preparaten van de Wet op
  de geneesmiddelenvoorziening (WOG))

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HISTORY / LEGISLATION OF GCP (2)

• 1998 (official February 27 effective March 18)
• ICH Guideline Guide for Good Clinical Practice
• incorporated in law
• (amendment to Article 55 of the Decree on the
• Preparation and Supply of Pharmaceutical
  Products of
• the Law on Drug Supply Besluit bereiding en
  afleveringvan farmaceutische preparaten van de
  Wet op
  de geneesmiddelenvoorziening (WOG))

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HISTORY / LEGISLATION OF GCP (3)

• 1999 (official 1998 effective December 01)
• Law on Medical Research in Human
• (Wet Medisch-wetenschappelijk Onderzoek met
  mensen WMO)
• Totally revised version approved by the House
  Tweede Kamer December 16, 2003
  (Directive 2001/20/EC incorporated
• N.B. amended by the Senate Eerste Kamer)
• Official March 01, 2006

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HISTORY / LEGISLATION OF GCP (4)

• In WMO among others
• Extensive description of the important role of
  Medical Ethics Committees

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MEDICAL ETHICAL REVIEW ACCORDING TO WMO

• Dual review system (can be performed in parallel)
• centralized procedure (bevoegde autoriteit
  the competent authority)
  
  CCMO in The Hague (Centrale Commissie
  Mensgebonden Onderzoek Central Committee Human
  Research)
• decentralized (local) procedure (Local Medical
  Ethics Committee METCs) METC that has been
  approved by CCMO (a so called Erkende Medisch
  Ethische Toetsings Commissie Accredited
  Medical Ethics Committee)

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MEDICAL ETHICS COMMITTEES (1)

• General speaking
• CCMO performs a marginal review
• Local Medical Ethics Committee performs the main
  review

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MEDICAL ETHICS COMMITTEES (2)

• Both the Central Committee (CCMO) and the local
  committees are independent administrative
  agencies (governing bodies) ZBO
  Zelfstandig Bestuurs Orgaan
• official bodies
• have power to make judgements that are binding on
  citizens(in this case, judgements under the
  Dutch WMO)

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (1)

• Established according to Article 14 of the WMO
  on April 06, 1999
• Members (maximum of 14)
• one or more physicians
• experts in
• embryology
• pharmacology
• nursing
• behavioural science
• jurisprudence
• methodology of scientific research and ethics
• member that reviews from the participants point
  of view
• hospital pharmacy
• genetic therapy

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (2)

• Members are proposed by Minister of
  Health,Welfare and Sport
• Appointed by Queen (royal degree)
• For a term of 4 years (can be re-appointed up to
  2 times)

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (3)

• TASKS
• 1Coordinating and supervising all medical
  ethical review in The Netherlands
• Certification (accreditation) of local Medical
  Ethics Committees
• Makes inventory of clinical research performed in
  The Netherlands
• Performs a marginal review of submitted documents

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (4)

• Being the competent authority in The
  Netherlands CCMO will perform a so called
  marginal review of each study proposal that has
  been reviewed by a METC
• Checks the following items
• EudraCT number
• completeness of submitted documentation
• side effects of IMP ( Investigational Medicinal
  Product) as far as present in the EU-database
  (Eudra Vigilance EMEA)
• inspection reports (GCP and GMP)
• (website www.ccmo.nl)

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (5)

• Time frame 14 days
• If approved, CCMO has to issue a Verklaring van
  Geen Bezwaar (Statement of No Objection)

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (6)

• CCMO also publishes several guidance documents
  for Sponsors, Investigators and METCs, e.g.
• Instruction Manual Clinical Research with
  Medicinal Products in The Netherlands (
  erratum)
• example IMPD (Investigational Medicinal Product
  Dossier)
• on Multicentre research
• External Review Directive
• several Forms

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (7)
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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (8)

• TASKS
• 2 Acts as real Medical Ethics Committee
  (according to Article 2b of the WMO) Performs
  the main review of all study proposals in case
  of
• non-therapeutic research in children and subjects
  unable to give informed consent
• gene therapy ?vaccine development
• xenotransplantation ?anti-sense oligonucleotides
• heroin addiction ?interference-RNA
• research on reproductive cells and embryos
• (somatic) cell therapy

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (9)

• Time frame 60 (30) days
• In case of approval the CCMO has to issue a
  Positive Opinion
• In those cases the Minister van Volksgezondheid,
  Welzijn en Sport Minister of Health, Welfare
  and Sport has to give a Statement of no
  Objection (because of the dual review system)
• Time frame
• Phase I 21 days
• Other Phases 49 days

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CENTRAL COMMITTEE HUMAN RESEARCH CCMO (10)

• Number of protocols reviewed in 2005
• 28, of which 9 were disapproved ( 31)
• 18 protocols on non-therapeutic studies with
  children or subjects unable to give informed
  consent
• 1 protocol on gene therapy
• 0 protocols on xenotransplantation
• 1 protocol on studies with heroin
• 4 protocols on studies with embryos
• 4 other protocols
• 6 protocols concerned drug studies ( 21)

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CCMO OR LOCAL MEDICAL ETHICS COMMITTEE?
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LOCAL MEDICAL ETHICS COMMITTEES (1)

• 34 committees accredited by CCMO (2005)

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LOCAL MEDICAL ETHICS COMMITTEES (2)

• METC will perform the main review an extensive
  review of the total impact of the study proposal
  and the Investigational Medicinal Product (IMP)
  including
• the relevance of the clinical trial and the trial
  design
• evaluation of anticipated benefits and risks
• suitability of the Investigator and supporting
  staff

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LOCAL MEDICAL ETHICS COMMITTEES (3)

• Further items of review by METC are
• pharmacology / toxicology
• pharmaceutical quality of the Investigational
  Medicinal Product
• financial information
• insurance of study participants
• liability insurance
• honorarium (Investigators and study participants)
• arrangements for the recruitment of subjects

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LOCAL MEDICAL ETHICS COMMITTEES (4)

• METC has to review the following documents
  (o.a.)
• Clinical Trial Protocol
• Investigators Brochure (IB)
• Investigational Medicinal Product Dossier (IMPD)
• information that will be given to patient /
  volunteer
• Informed Consent Form

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LOCAL MEDICAL ETHICS COMMITTEES (5)

• The total dossier which has to be reviewed should
  also contain
• survey of trials with the same IMP which are
  (have been) performed in others centers
• experts opinion of external consultants (e.g.
  RIVM / TNO)
• samples of labels (with Dutch text)
• Curriculum Vitae of all Investigators
• statement of compliance with GCP principles
• Information on facilities
• statement that study can be performed (Lokale
  Uitvoerbaarheids Toets)

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LOCAL MEDICAL ETHICS COMMITTEES (6)

• METC has a time frame of 60 days (the clock can
  be stopped once with a request for additional
  information)
• METC has to issue a Positieve Opinie
  (Positive Opinion)

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LOCAL MEDICAL ETHICS COMMITTEES (7)

• The Local Medical Ethics Committees gave in 2005
  a judgment on 1720 Study Protocols (645 drug
  studies) of which 1158 studies (371 drug studies)
  in academic hospitals
  rest
  peripheral hospitals and Contract Research
  Organizations (in 2005)
• 14 protocols were rejected ( 0.8 in 2005)

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LOCAL MEDICAL ETHICS COMMITTEES (8)

• Multicentre / single country
  For a multicentre trial to be
  performed in one Member State approval of one
  METC is sufficient (Single Opinion)

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LOCAL MEDICAL ETHICS COMMITTEES (9)

• Multicentre / multi country
  For a multicentre trial to be
  performed in more than one Member State approval
  of one METC per Member State is required

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LOCAL MEDICAL ETHICS COMMITTEES (10)

• Lokale Uitvoerbaarheids Toets (Check if the
  trial can be performed in the hospital /
  institution)
• has to be performed by Board of Directors of the
  organization (staff competent? enough capacity?
  insurance!)
• has to be reported in writing to the METC
• time frame within 30 days

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MEDICAL ETHICS COMMITTEES (1)

• QUALITY MANAGEMENT (1)
• CCMO checks METCs
• composition ( experts knowledge of each of the
  members)
• performance
• CCMO coordinates the set up of a SOP-system for
  METCs (templates for SOPs)
• CCMO has many standard forms to be used by
• METC
• Sponsor

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MEDICAL ETHICS COMMITTEES (2)

• QUALITY MANAGEMENT (2)
• NVMETC (Nederlandse Vereniging van Medisch
  Ethische Toestings Commissies Dutch
  Associationof Medical Ethics Committees)
  performs site-visits (audits) at local METCs
• IGZ (Inspectie Gezondheids Zorg Health
  Inspectorate) performs GCP-inspections at
• CCMO
• METCs

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IMPACT OF NEW REGULATIONS (1)

• Impact is relative small due to the fact that
  thereexcists a
• a very well functioning system of (dual) ethical
  review for many years, especially after the
  introduction of the WMO (1999)
• due to strict accreditation system the standard
  is high METCs are very professional
• There have been many changes ( improvements)
  but that occurred immediately after
• legal introduction of ICH-GCP (1998)
• the introduction of the WMO (1999) (gave a boost
  to improvement of quality)

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IMPACT OF NEW REGULATIONS (2)

• Some of the new items are (1)
• EudraCT database
• CCMO has to make sure that the study proposal has
  been entered in the EudraCT database
• Dual review system
• main review by local METC
• marginal review by CCMO

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IMPACT OF NEW REGULATIONS (3)

• Some of the new items are (2)
• Deadlines
• for main review of study proposal (all
  documents) 60 days (was 112 days)
• for an amendment 35 days (was 112 days)
• for marginal review 14 days
• Additional expertise
• for WMO-drug studies the METC has to have a
  (hospital) pharmacist and a clinical
  pharmacologist among the members

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IMPACT OF NEW REGULATIONS (4)

• Some new tasks had impact on the work of the
  members of the METCs
• review of the IMPD (Investigational Medicinal
  Product Dossier) (therefore the judgement of a
  (hospital) pharmacist and a clinical
  pharmacologist is required)
• CCMO can require additional training of members
  of METC
• a special training course was set up (NOMET,
  Maastricht)

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CONCLUSIONS (1)

• In The Netherlands excists a very professional
  system of medical ethical review for many years
• Quality of the METCs was boosted by
• introduction of ICH-GCP in Dutch law (1998)
• introduction of an extensive law on medical
  research in humans (WMO 1999)
• the strong coaching performance of the Central
  Committee Human Research (CCMO 1999)
• the activities of a national association of
  METCs (NVMETC including audits)
• a well established GCP-inspection system (1993)

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CONCLUSIONS (2)

• Overall the introduction of e.g. European
  Directives (2001/21/EC and 2005/28/EC) had
  relative limited impact