ethical review 20060915 1/46 jhgj/gh the changing nature of ethical review prof. janhasker g....

ETHICAL REVIEW 20060915 1/46

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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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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

CLINICAL RESEARCH (1)


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• 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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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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• 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))

HISTORY / LEGISLATION OF GCP (1)


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• 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 aflevering

van farmaceutische preparaten van de Wet op de geneesmiddelenvoorziening (WOG))



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• 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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In WMO among others

• Extensive description of the important role of Medical Ethics Committees



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• 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; METC’s): METC that has been approved by CCMO (a so called ‘Erkende Medisch Ethische Toetsings Commissie’ = Accredited Medical Ethics Committee)

MEDICAL ETHICAL REVIEW ACCORDING

TO WMO


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General speaking:

• CCMO performs a marginal review• Local Medical Ethics Committee performs

the main review

MEDICAL ETHICS COMMITTEES (1)


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• 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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• 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

CENTRAL COMMITTEE HUMAN RESEARCH –

CCMO (1)


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• 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)


CCMO (2)


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TASKS:

• 1:Coordinating 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


CCMO (3)


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• 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)


CCMO (4)


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• Time frame: 14 days

• If approved, CCMO has to issue a ‘Verklaring van Geen Bezwaar’ (‘Statement of No Objection’)


CCMO (5)


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• CCMO also publishes several guidance documents for Sponsors, Investigators and METC’s, 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


CCMO (6)


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CCMO (7)


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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


CCMO (8)


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• 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


CCMO (9)


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• 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%)


CCMO (10)


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CCMO OR LOCAL MEDICAL ETHICS

COMMITTEE?


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• 34 committees accredited by CCMO (2005)

LOCAL MEDICAL ETHICS COMMITTEES (1)


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



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• 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

expert’s 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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• 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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• 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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• 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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• 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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• ‘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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QUALITY MANAGEMENT (1)

• CCMO checks METC’s composition (+ experts knowledge of each of the members) performance

• CCMO coordinates the set up of a SOP-system for METC’s (templates for SOP’s)

• CCMO has many standard forms to be used by METC Sponsor



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QUALITY MANAGEMENT (2)

• NVMETC (Nederlandse Vereniging van Medisch Ethische Toestings Commissies; Dutch Associationof Medical Ethics Committees) performs site-visits (‘audits’) at local METC’s

• IGZ (Inspectie Gezondheids Zorg; Health Inspectorate) performs GCP-inspections at CCMO METC’s



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• 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: METC’s 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)

IMPACT OF NEW REGULATIONS (1)


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• 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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• 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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• Some new tasks had impact on the work of the members of the METC’s 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 METC’s 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 METC’s

(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

ethical review 20060915 1/46 jhgj/gh the changing nature of ethical review prof. janhasker g....

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