79C3C34C52B45572883A05D425EB0F82
Opinion No. 51: Publication of the Results of Human Experimentation (2012)
https://www.health.belgium.be/sites/default/files/uploads/fields/fpshealth_theme_file/opinion_51web.pdf
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / political affiliation
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p.000019: Commissie voor Mensgebonden Onderzoek, CCMO)
p.000019: On 13 November 2008, the Dutch Central Commission for research involving human subjects (Centrale
p.000019: Commissie voor Mensgebonden Onderzoek, CCMO) published the ‘Research contract assessment’ directive
p.000019: (Richtlijn ‘Beoordeling onderzoekscontract’) intended for medical-ethical assessment committees (Medisch-ethische
p.000019: toetsingscommissies, METC), which entered into force in 2009. In 2010, this directive was assessed, resulting on 30
p.000019: August 2011 in the revised ‘Research contract assessment’ directive65. Article 3 became Article 4, in which point c)
p.000019: was reworded and point d) added.
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019: 65 Revised CCMO ‘Research contract assessment’ directive of 30 August 2011:
p.000019: www.ccmo- online.nl/hipe/uploads/downloads_catc/CCMO%20jaarverslag%202010.PDF
p.000019: (initial CCMO ‘Research contract assessment’ directive of 13 November 2008:
p.000019: www.ccmo- online.nl/hipe/uploads/downloads_catp/Staatscourant%20CCMO-richtlijn%20onderzoekscontracten.pdf)
p.000019:
p.000019: Final version
p.000020: 20
p.000020:
p.000020: (free translation66) “Article 4
p.000020: The contract may not include unreasonable limitations regarding the publication of research findings. Unreasonable
p.000020: limitations are deemed to mean in any case:
p.000020: a. the condition that publication is authorised only after the approval of the promoter or the
p.000020: investigator;
p.000020: b. the right of the promoter or the investigator to ban publication by another party without giving a
p.000020: reason for this or giving a reason that does not offset the importance of data publication;
p.000020: c. a ban on the publication of data or some data on condition that the planned publication is submitted to the other
p.000020: party when the period of application of this ban exceeds ninety days, subject to special conditions which may justify a
p.000020: longer period;
p.000020: d. a ban or limitations on the publication of data or some data which is extended beyond twelve months after the end of
p.000020: the research in the absence of publication of the findings;
p.000020: e. an exclusive right of publication for the promoter or the investigator unless this is not considered
p.000020: unreasonable in a given situation.”
p.000020: This article is accompanied by the following comment: (free translation)
p.000020: “The directive notes […] that unreasonable limitations on publication are unacceptable […]. The
p.000020: contracting parties are of course free to agree terms of publication provided that the starting point is that the
p.000020: data will be made publicly available and that one of the parties does not have its possibilities of publishing the
p.000020: findings itself unreasonably limited. The limitation that, in the event of multi- centre research, individual
p.000020: researchers will not publish their findings until after the central publication of all the data may be
p.000020: considered reasonable, provided that this central publication takes place within a reasonable period of
p.000020: time. A period of longer than 12 months will be considered unreasonable in this respect. A promoter may also stipulate
p.000020: that publications planned by researchers should first be submitted to the promoter so that he can react to
p.000020: them within a
p.000020:
p.000020: 66 Original version:
p.000020: “Artikel 4
p.000020: In de overeenkomst mogen geen onredelijke beperkingen zijn opgenomen ten aanzien van de openbaarmaking van de
p.000020: resultaten van het onderzoek. Als onredelijke beperkingen worden in elk geval opgevat:
p.000020: a. de voorwaarde dat openbaarmaking alleen is toegestaan na goedkeuring door de verrichter of uitvoerder;
p.000020: b. een recht van de verrichter of uitvoerder om openbaarmaking door de ander te verbieden zonder opgaaf van redenen of
p.000020: onder opgaaf van redenen die niet opwegen tegen het belang van openbaarmaking van de gegevens;
p.000020: c. een verbod op openbaarmaking van de gegevens of een deel daarvan onder de voorwaarde dat de voorgenomen
p.000020: openbaarmaking aan de andere partij moet worden voorgelegd, wanneer de termijn waarvoor dit verbod geldt meer dan
p.000020: negentig dagen is, behoudens bijzondere omstandigheden die een langere termijn kunnen rechtvaardigen;
p.000020: d. een verbod op of beperkingen ten aanzien van openbaarmaking van de gegevens of delen daarvan dat voortduurt nadat
p.000020: twaalf maanden zijn verstreken na beëindiging van het onderzoek en publicatie van de resultaten is
p.000020: uitgebleven;
p.000020: e. een alleenrecht op openbaarmaking van de verrichter of uitvoerder, tenzij dat in de gegeven omstandigheden als niet
p.000020: onredelijk moet worden beschouwd.”
p.000020: The distinction between ‘verrichter’ and ‘uitvoerder’ is defined in Article 1 of the Dutch act of 26 February 1998 on
p.000020: medical-scientific research on humans (Wet houdende regelen inzake medisch-wetenschappelijk onderzoek met
p.000020: mensen, WMO), as revised on 1 March 2006:
p.000020: (verrichter) “f. the party accomplishing the scientific research: person, company, institution or organisation that
p.000020: takes responsibility for the launch, management or funding of the scientific research”, this corresponds
p.000020: to the definition of ‘promoter’ in the Belgian act of 7 May 2004 on human experimentation;
p.000020: (uitvoerder) “g. the party carrying out the scientific research: doctor or person referred to in Article 3, e, in
p.000020: charge of carrying out the scientific research at a given site. If the actual carrying out of the
p.000020: research is entrusted to an employee or other auxiliary, the party uses this person is deemed to be the one
p.000020: carrying out the scientific research’, which corresponds to the definition of ‘investigator’ in the Belgian act of 7
p.000020: May 2004 on human experimentation.
p.000020: Original version:
p.000020: “f. degene die het wetenschappelijk onderzoek verricht: een persoon, bedrijf, instelling of organisatie
p.000020: die de verantwoordelijkheid op zich neemt voor het starten, het beheer of de financiering van het
p.000020: wetenschappelijk onderzoek;
p.000020: g. degene die het wetenschappelijk onderzoek uitvoert: een arts of een in artikel 3, onder e, bedoelde persoon, die
p.000020: verantwoordelijk is voor de uitvoering van het wetenschappelijk onderzoek op een bepaalde locatie. Indien
p.000020: de feitelijke uitvoering geschiedt door een werknemer of een andere hulppersoon, wordt degene die van deze persoon
p.000020: gebruik maakt aangemerkt als degene die het onderzoek uitvoert.”
p.000020:
p.000020: Final version
p.000021: 21
p.000021:
p.000021: reasonable period of time or has, for instance, had the opportunity to submit patent applications. It is
p.000021: important for the parties to succeed in resolving any differences of opinion together and for none of the
p.000021: parties concerned to have a veto.”
p.000021:
p.000021: The Dutch CCMO thus expressly gives the medical-ethical assessment committees (METC) the task of checking
p.000021: whether research agreements contain unreasonable limitations on the publication of research findings.
p.000021: Moreover, the same directive aims to limit the premature interruption of scientific research projects (Article 3) to
p.000021: the extent that, in the context of these projects, trial subjects have already been subjected to experimental
p.000021: interventions.
...
Searching for indicator political:
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p.000006: gevolgen voor de richtlijn ‘Depressie’”, Ned Tijdschr Geneeskd., 2008, 21 June, 152(25), pp. 1406-1408.
p.000006: 14 McGauran N, Wieseler B, Kreis J, Schüler Y-B, Kölsch H, Kaiser T. (2010), “Reporting bias in medical research – a
p.000006: narrative review”, Trials, 2010, 11:37, 15 p.
p.000006: See web page: www.trialsjournal.com/content/11/1/37
p.000006: This article includes a list of over 250 reference articles, some of which restate the references given in the NIHR
p.000006: report 2010.
p.000006:
p.000006: Final version
p.000007: 7
p.000007:
p.000007: were underreported, positive secondary outcomes were highlighted rather than negative primary outcomes15.
p.000007: Numerous studies have been conducted comparing publication bias. The NIHR report 2010 contains a list of 537
p.000007: reference articles. One of the objectives of the health technology assessment was in fact to identify
p.000007: and assess empirical studies on publication bias and related bias published as of 1998.
p.000007:
p.000007: It is also important that the outcome variables or the assessment criteria in the context of a clinical study are
p.000007: chosen carefully and that the limitations on variables or criteria are explained. Hochman et McCormick16
p.000007: thus stress that without any explanation of their limitations, the use of substitution criteria 17 or combined
p.000007: assessment criteria rather than clinical criteria, or of mortality due to illness rather than total mortality or the
p.000007: reporting of relative risks rather than absolute risks can lead to biased findings, which complicates the way they are
p.000007: interpreted by the doctors, the patients and the political decision-makers.
p.000007:
p.000007: An article by Lexchin et al.18 states that studies of medicinal products sponsored by pharmaceutical
p.000007: companies generate more positive research findings than the same studies on medicinal products conducted by
p.000007: researchers who are not working on behalf of the pharmaceutical industry.
p.000007: In his article, Steen19 indicates that 85 % of clinical trials sponsored by the industry result in positive findings,
p.000007: as against 50 % for studies financed by public funds. It is also possible that this is linked to the fact that the
p.000007: industry examines more advanced study phases when a positive outcome is more probable than in the initial phase
p.000007: of a research project.
p.000007:
p.000007: Need for adequate reporting
p.000007:
p.000007: It is important to report clinical trials adequately for both scientific and ethical reasons.20 Failing to publicly
p.000007: disclose findings that are ‘unfavourable’, ‘of no interest’, or not presenting sufficiently detailed
p.000007: findings (underreporting/selective reporting) can mean that patients are given treatment that is ineffective, or even
p.000007: harmful, for longer than is necessary or that they are refused a more effective treatment for longer than is
p.000007: necessary.21
p.000007:
p.000007:
p.000007:
p.000007: 15 First of all, the primary and secondary outcome variables defined in advance – that is prior to the execution of the
p.000007: research – must be distinguished from outcome variables determined by ‘post hoc analysis’. The definition
p.000007: given below concerns the outcome variables cited first: see www.consort-statement.org/resources/glossary/m---
p.000007: p/outcome-primary-and-secondary/:
...
Health / Drug Usage
Searching for indicator drug:
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p.000003: legislator took the definition of clinical trial as formulated in the directive (Article 2, 7°):
p.000003:
p.000003: “clinical trial: any investigation in human subjects intended to discover or verify the clinical, pharmacological
p.000003: and/or other pharmaco-dynamic effects of one or more investigational medicinal product(s) and/or to
p.000003: identify any adverse reactions to one or more investigational medicinal products and/or to study
p.000003: absorption, distribution, metabolism and excretion of one or more investigational medicinal
p.000003: products with the object of ascertaining its (their) safety and/or efficacy”.
p.000003:
p.000003: However, the scope of application of the Belgian act covers far more than simply interventional
p.000003: studies with medicinal products, as can be seen from the following definition of the concept of 'experimentation’ in
p.000003: Article 2, 11:
p.000003:
p.000003: “Experimentation: trial, study or investigation in human subjects intended to develop knowledge specific to the
p.000003: exercising of health-care professions as referred to by Royal Decree No 78 of 10 November 1967 on the exercising of
p.000003: health-care professions.”
p.000003:
p.000003: The act provides for an exception to Article 3, §21: purely retrospective studies do not fall within the scope of
p.000003: application of the act.
p.000003:
p.000003: It will be seen later in the opinion that the Dutch legislator has also introduced broader regulation of
p.000003: medical-scientific research than that provided for in the European directive.
p.000003: The Food and Drug Administration (FDA) in the United States also adopts a broader definition of a
p.000003: clinical trial than that formulated in the European directive. The Council of Europe and the World Health
p.000003: Organisation go even further in this definition.
p.000003:
p.000003: In the following text, the term 'clinical trials' should be interpreted in the broad sense, that is in the sense of
p.000003: research carried out on humans, which also corresponds more closely to the scope of application of Belgian law, that is
p.000003: experiments conducted on human subjects that contribute towards the development of knowledge specific to the exercising
p.000003: of health-care professions. When reference is made to European Directive 2001/20/EC, this therefore refers only to
p.000003: interventional studies concerning medicinal products (see also the aforementioned definition of a clinical trial in
p.000003: Belgian law).2
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 Art. 3, §2: “This law does not apply to purely retrospective studies based on past data which are found in patients’
p.000003: dossiers, medical dossiers or administrative dossiers or databases provided that under no circumstances are new data
p.000003: relating to these patients found.”
p.000003: 2 In the introductory report for opinion No 13 of 9 July on human experimentation, the Committee defines the
p.000003: concept of experimentation in point B. It also explains the various phases of biomedical experimentation relating to
p.000003: substances that may be medicinal products, which corresponds to an interventional study concerning
p.000003: medicinal products in this opinion.
p.000003: See web page:
...
p.000005: trials of new oncology drugs”, Trials, 10:116, see p. 4.
p.000005: See web page: www.trialsjournal.com/content/10/1/116. 7 NIHR report 2010, p. 2.
p.000005: 8 Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ. (2000), “Publication and related biases”, Health Technol Assess,
p.000005: 4(10), 115 p.
p.000005: For the full report, see web page http://www.hta.ac.uk/project/1051.asp.
p.000005:
p.000005: Final version
p.000006: 6
p.000006:
p.000006: which produce conclusive or positive findings are disseminated more and more quickly9 than studies whose
p.000006: findings are inconclusive or negative.10
p.000006: The 2010 update reaches a similar conclusion11, i.e. that the dissemination of research findings is a
p.000006: biased process the real impact of which is unknown. This should be taken into account when taking evidence-based
p.000006: decisions. This updated version makes reference to recent initiatives to promote the prospective registration of
p.000006: clinical trials and guidelines on the reporting of research findings, while stressing that the prospective registration
p.000006: of basic research, the early phases12 of clinical trials and observations has not yet been sufficiently developed.
p.000006: Prospective registration only helps reduce publication bias when the findings of the studies registered are also
p.000006: accessible. For systematic reviews, the proposal is to systematically examine the studies published and
p.000006: not published in order to reduce the impact of publication bias.
p.000006:
p.000006: Examples of studies of the phenomenon of underreporting and related problems giving rise to biased information in
p.000006: medical-scientific literature.
p.000006:
p.000006: In a study by Turner et al.13, the reports from the American Food and Drug Administration (FDA) on clinical trials
p.000006: registered with the FDA concerning twelve antidepressants were compared with the findings that had been
p.000006: published in scientific reviews. Of the 74 clinical trials registered – in which a total of 12,564 patients
p.000006: had participated – nothing was published in 31 % of cases (~3.449 trial subjects). Virtually all the studies
p.000006: published (94 %) yielded positive findings whereas, on the basis of all the reports from the FDA – that is both
p.000006: published and unpublished data – only half (51 %) were positive. Of the 36 studies that produced negative
p.000006: or doubtful findings, 22 were not published. Of the 14 studies actually published, the findings were wrongly presented
p.000006: as positive in 11 cases. This study therefore noted not only the underreporting of research findings with a publication
p.000006: bias in favour of clinical trials with positive findings, but also a distortion of the findings themselves: study data
p.000006: with negative findings were presented in the publications in such a way that the findings seemed positive.
p.000006:
p.000006: Another example referred to in an article by McGauran et al.14 concerns a study of 900 clinical trials
p.000006: relating to 90 new medicinal products approved by the American FDA. The findings of just 43 % of the
p.000006: clinical trials were published. Moreover, selective reporting of the findings was observed in the publications:
p.000006: negative findings were presented in a positive fashion, the conclusions did not appear to be backed up by the
p.000006: findings, the side effects
p.000006:
p.000006:
p.000006:
p.000006:
p.000006:
p.000006: 9 The broader concept of ‘diffusion’ or ‘dissemination’ is used in the NIHR report, to the extent that publication in a
...
p.000010: actions, the rare or belated side effects, etc.”
p.000010: 33 NIHR report 2010, p. 83.
p.000010: See also Annex 3, point 3. Scope of application: “The information to be included in the EudraPharm database further to
p.000010: section 4 covers clinical trials, phases II, III et IV, (…).”
p.000010:
p.000010: Final version
p.000011: 11
p.000011:
p.000011: The European Union (EMA)
p.000011:
p.000011: Protocols on interventional clinical trials with medicinal products that fall under the scope of application of
p.000011: European Directive 2001/20/EC, must be registered prospectively in the EudraCT database. In early 2011, the
p.000011: Clinical Trials Register34 was launched in which the European Medicines Agency (EMA) makes public several field of
p.000011: information in the EudraCT database. The European Commission describes the interest of this procedure as follows:
p.000011: “This information is potentially useful for patients, care staff and the health professionals, who may be
p.000011: interested in the trials that are underway and trials that have already been carried out. Moreover, more transparent
p.000011: information can contribute towards the development of research and thus guarantee the devising of better quality
p.000011: trials, requiring the participation of a smaller number of patients and avoiding all needless duplication. The
p.000011: pharmaceutical industry, university and scientific circles as well as the regulatory bodies are other potential users
p.000011: of this type of information.”35
p.000011: The United States (FDA)
p.000011:
p.000011: In the United States, since February 2000 there has been a similar public register at the Food and Drug
p.000011: Administration (FDA) where clinical trials are recorded before they begin, see www.clinicaltrials.gov.
p.000011:
p.000011: The World Health Organisation (WHO)
p.000011:
p.000011: The World Health Organisation is also endeavouring, with its International Clinical Trials Registry
p.000011: Platform (ICTRP) to produce a comprehensive list of clinical trials with a view to guaranteeing greater
p.000011: transparency and validity of evidence-based scientific knowledge.36 The WHO also defines a clinical trial more broadly
p.000011: than European Directive 2001/20/EC (see also Annex 1, B.2.).
p.000011:
p.000011: The Netherlands (CCMO)
p.000011:
p.000011: Like Belgium, the Netherlands has national legislation with a wider scope of application than that of European
p.000011: Directive 2001/20/EC.
p.000011: In the Netherlands, the Dutch Central Commission for research involving human subjects (Centrale Commissie
p.000011: voor Mensgebonden Onderzoek, CCMO) collects, data from research protocols assessed by recognised medical-ethical
p.000011: assessment committees (Medisch-ethische toetsingscommissies, METC), as well as their decisions
p.000011: via the portal https://ToetsingOnline.ccmo.nl. For new studies which, as of 1 November 2009, are
p.000011: submitted for assessment to the METC, the basic data from the Algemeen Beoordeling- en Registratieformulier
p.000011: (ABR-formulier, General assessment and registration form) are automatically made public as soon as
p.000011: they are entered into ToetsingOnline by the METC which assessed the study. As of 2010, a exception is made
p.000011: for phase-1 studies: the basic data from the ‘ABR’ form are not automatically made public when entered ToetsingOnline
p.000011: by the METC concerned, but six months later37. (See Annex 1, C.).
...
p.000014: British Medical Journal. His proposal consists of publishing the protocols of studies and their findings
p.000014: in an online register only, and publishing solely articles that discuss the validity of these studies in
p.000014: scientific periodicals. This may seem to be a curious solution, but according to the two authors, it has not really
p.000014: been proved that peer review results in clearly better reporting of research findings.51
p.000014: In this context, the NIHR report 2010 points out that electronic publication offers the possibility of
p.000014: unlimited publication space so that more information and data could be made accessible. Studies could thus be judged on
p.000014: their design and methodology, as well as the immediate relevance of findings in practice. The editors of
p.000014: electronic reviews could also encourage the publication of studies with negative or inconclusive findings. 52
p.000014: Finally, it may be asserted that transparency is also essential to detect scientific fraud, such as deliberately
p.000014: holding back negative findings or the distortion of research data.
p.000014:
p.000014: Existing initiatives, points of view and existing guidelines
p.000014:
p.000014: There also follows a non-exhaustive survey of a certain number of initiatives and existing points of
p.000014: view/guidelines at international and European level to promote the publication of research findings. Some of these are
p.000014: covered exhaustively in Annex 1.
p.000014:
p.000014: The United States (FDA)
p.000014:
p.000014: As indicated above, since February 2000 there has been a public register in the United States in which clinical
p.000014: trials are registered before they start. In 2007, the Food and Drug Administration Amendments Act (27
p.000014: September 2007) expanded this register to include the findings of these clinical trials. (See also Annex 1, B.1.).
p.000014: In addition, in 2011, a sub-committee of the US Presidential Commission for the Study of Bioethical Issues,
p.000014: that is the ‘International Research Panel’ recommended in particular53
p.000014:
p.000014:
p.000014: 48 Idem, see pp. 25-26.
p.000014: 49 NIHR report 2010, pp. 51-52.
p.000014: 50 Spielmans GI, Parry PI. (2010), “From evidence-based medicine to marketing-based medicine: evidence
p.000014: from internal industry documents”. Journal of Bioethical Inquiry, Springer, 2010(7), pp. 13-29, see p. 26.
p.000014: 51 Idem, see p. 26 [with reference to Jefferson T, Rudin M, Brodney Folse S, Davidoff F. (2007) “Editorial peer review
p.000014: for improving the quality of reports of biomedical studies”, Cochrane Database of Systematic Reviews 2].
p.000014: 52 NIHR report 2010, pp. 52-53.
p.000014: See also Chalmers I. “Underreporting research is scientific misconduct, abridged version in Ethical and regulatory
p.000014: aspects of clinical research: readings and commentary, Ezekiel JE et al., Johns Hopkins University Press 2003, pp.
p.000014: 411-414, see pp. 413-414.
p.000014: See also Sandercock P. (2011 copyright) “Negative results: why do they need to be published?”, International Journal of
p.000014: Stroke, Vol. 7, January 2012, pp. 32-33, see p. 33.
p.000014: Web page: onlinelibrary.wiley.com/doi/10.1111/j.1747-4949.2011.00723.x/full.
p.000014: 53 “US commission recommends increased protection for people in research after reviewing 1940s syphilis study”,
p.000014: BMJ 2011; 343.d5577 (published 2 September 2011) – original version:
...
Searching for indicator influence:
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p.000006: with negative findings were presented in the publications in such a way that the findings seemed positive.
p.000006:
p.000006: Another example referred to in an article by McGauran et al.14 concerns a study of 900 clinical trials
p.000006: relating to 90 new medicinal products approved by the American FDA. The findings of just 43 % of the
p.000006: clinical trials were published. Moreover, selective reporting of the findings was observed in the publications:
p.000006: negative findings were presented in a positive fashion, the conclusions did not appear to be backed up by the
p.000006: findings, the side effects
p.000006:
p.000006:
p.000006:
p.000006:
p.000006:
p.000006: 9 The broader concept of ‘diffusion’ or ‘dissemination’ is used in the NIHR report, to the extent that publication in a
p.000006: scientific review is only one of the possible ways of disseminating research findings, see NIHR report 2010, p. 2.
p.000006: See also Rennie D. (2008), “The obligation to publish and disseminate results”, in The Oxford textbook of clinical
p.000006: research ethics, Ezekiel J.E. et al., Oxford University Press, pp. 795-807, see p. 796.
p.000006: 10 NIHR report 2010, p. 1.
p.000006: 11 NIHR report 2010, pp. III and XI.
p.000006: 12 NIHR report 2010, p. 83: “Efforts so far have focused on the registration, publication and
p.000006: disclosure of confirmatory phase III/IV trials due to the perceived immediate consequences”. This does not, however,
p.000006: mean that for subsequent phases of clinical trials, there is no longer any distortion of research results.
p.000006: 13 Turner EH, Matthews AM, Linardatos E, Tell RA, and Rosenthal R. (2008), “Selective publication of antidepressant
p.000006: trials and its influence on apparent efficacy”, New England Journal of Medicine 358, pp. 252-260.
p.000006: See also Doornbos B, de Jonge P, Bockting CLH. (2008), “Selectieve publicatie van onderzoek met antidepressiva:
p.000006: gevolgen voor de richtlijn ‘Depressie’”, Ned Tijdschr Geneeskd., 2008, 21 June, 152(25), pp. 1406-1408.
p.000006: 14 McGauran N, Wieseler B, Kreis J, Schüler Y-B, Kölsch H, Kaiser T. (2010), “Reporting bias in medical research – a
p.000006: narrative review”, Trials, 2010, 11:37, 15 p.
p.000006: See web page: www.trialsjournal.com/content/11/1/37
p.000006: This article includes a list of over 250 reference articles, some of which restate the references given in the NIHR
p.000006: report 2010.
p.000006:
p.000006: Final version
p.000007: 7
p.000007:
p.000007: were underreported, positive secondary outcomes were highlighted rather than negative primary outcomes15.
p.000007: Numerous studies have been conducted comparing publication bias. The NIHR report 2010 contains a list of 537
p.000007: reference articles. One of the objectives of the health technology assessment was in fact to identify
p.000007: and assess empirical studies on publication bias and related bias published as of 1998.
p.000007:
p.000007: It is also important that the outcome variables or the assessment criteria in the context of a clinical study are
p.000007: chosen carefully and that the limitations on variables or criteria are explained. Hochman et McCormick16
p.000007: thus stress that without any explanation of their limitations, the use of substitution criteria 17 or combined
p.000007: assessment criteria rather than clinical criteria, or of mortality due to illness rather than total mortality or the
p.000007: reporting of relative risks rather than absolute risks can lead to biased findings, which complicates the way they are
...
Health / Healthy People
Searching for indicator healthy volunteers:
(return to top)
p.000009: 30 CCMO Annual report 2010, p. 32.
p.000009: 31 See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”,
p.000009: Australian Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009:
p.000009: Final version
p.000010: 10
p.000010:
p.000010: As explained in the following point, the interest of the prior or prospective registration of clinical trials (phase
p.000010: II, III and IV trials32) is acknowledged on various sides. As regards the disclosure of information on phase I trials
p.000010: or first-into-man studies, however, there is more discussion.33
p.000010: Existing initiatives, points of view and guidelines
p.000010:
p.000010: There follows a non-exhaustive survey of a number of initiatives and points of view/guidelines
p.000010: concerning the prospective registration of research protocols. Some of these are covered in more detail in Annex 1.
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010: 32 The four successive phases of clinical trials are described in the introductory report to Opinion No 13 of 9 July
p.000010: 2001 on human experimentation, issued by the Committee, as follows (see point B. Definitions):
p.000010: “Phase I involves administering the product for the first time, in principle to a small number of volunteers in good
p.000010: health [editor’s note: often healthy volunteers, but not always, for example in the case of anti-cancer products], to
p.000010: assess their tolerance to the product, determine the maximum tolerated by humans and the minimum active dose of the
p.000010: product, and study its pharmacokinetic and pharmaco-dynamic properties.
p.000010: Phase II concerns trails on a limited group of patients suffering from the pathology for which the
p.000010: product is intended, in order to confirm its efficacy, assess its therapeutic interest, assess the relationship
p.000010: between the risks and the advantages linked to its administration and seek the best dose and the best
p.000010: means of administration depending n the effect sought.
p.000010: During phase III, studies are conducted on a large number of patients, usually divided into comparable
p.000010: groups, according to a strict methodology (randomisation). These studies aim to examine tolerance in the medium term
p.000010: and efficacy, so as to e able to estimate the relationship between the benefits and the disadvantages (unwanted effects
p.000010: and cost). This phase is also used to gather information which will be useful for prescribers. If it proves conclusive,
p.000010: the next step is to think about marketing the product and fulfilling the procedures to issue the authorisation to
p.000010: place it on the market.
p.000010: Phase IV comprises the studies conducted once the product has been put on the market. These studies are sued to gain
p.000010: better knowledge of the product: the possible association with other therapeutics, the discovery of new
p.000010: actions, the rare or belated side effects, etc.”
p.000010: 33 NIHR report 2010, p. 83.
p.000010: See also Annex 3, point 3. Scope of application: “The information to be included in the EudraPharm database further to
p.000010: section 4 covers clinical trials, phases II, III et IV, (…).”
...
Searching for indicator volunteers:
(return to top)
p.000007: medication trials”, Gen Intern Med , 6(11):1246–52, DOI: 10.1007/s11606-011-1813-7.
p.000007: 17 Arterial tension figures with, as clinical criterion, morbidity/mortality – are an example of a substitution
p.000007: criterion.
p.000007: 18 Lexchin J, Bero LA, Djulbegovic B, Clark O. (2003) “Pharmaceutical industry sponsorship and research outcome and
p.000007: quality: systematic review, BMJ, 31 May 2003, vol. 329, pp. 1167-1170.
p.000007: 19 Steen GR. (2011), “Misinformation in the medical literature: what role do error and fraud play?” JMedEthics, 2011,
p.000007: vol. 37, pp. 498-503, see p. 502.
p.000007: 20 See Chalmers, I., “Underreporting research is scientific misconduct”, abridged version in Ethical and regulatory
p.000007: aspects of clinical research: readings and commentary, Ezekiel, J.E. et al., Johns Hopkins University Press, 2003, pp.
p.000007: 411-414, see p. 411-412. [The article was initially published in JAMA 263 (1990), pp.1405-1408]
p.000007: See also NIHR report 2010, p. X.
p.000007: See also Rennie D. (2008), “The obligation to publish and disseminate results”, in The Oxford textbook of clinical
p.000007: research ethics, Ezekiel JE et al., Oxford University Press, pp. 795-807, see p. 795.
p.000007: See also Strech D. (2012), “Normative arguments and new solutions for the unbiased registration and publication of
p.000007: clinical trials”, Journal of Clinical Epidemiology (Elsevier), 65 (2012) pp. 279-281 [Epub 2011 Oct 18/19] – web page:
p.000007: www.open-project.eu/publications.
p.000007: 21 See also NIHR report 2010, pp. 39-40.
p.000007:
p.000007: Final version
p.000008: 8
p.000008:
p.000008: Patients and healthy volunteers who take part in clinical trials make an important contribution
p.000008: to progress in scientific knowledge. Inadequate reporting and the non- publication of all the findings
p.000008: do not do justice to those who take part in trials voluntarily in a spirit of altruism.
p.000008: Another consequence of this may be that limited resources and funds are not used to best effect and are therefore
p.000008: wasted.
p.000008: Moreover, this jeopardises the integrity of scientific research. When striking research findings are more
p.000008: widely disseminated than inconclusive findings, this represents a threat to the validity of a research synopsis.22
p.000008: Which players are involved?
p.000008:
p.000008: The NIHR 2010 report stipulated that underreporting of research findings or a publication bias may result from a
p.000008: convergence of the interests of the researchers, peer reviewers, editors and sponsors, while at the same time
p.000008: pointing out that they may be responsible to differing degrees. Despite the fact that various complex
p.000008: factors play a role in the phenomenon of publication bias, the NIHR report states that it is possible
p.000008: to prevent publication bias to a certain extent and reduce its impact. The report puts forward measures to this end,
p.000008: including an adaptation of the policy on the publication of research findings, the possibility of electronic
p.000008: publication, an open access policy, the prospective registration of studies and the setting up of large-scale
p.000008: studies to confirm small-scale research findings.23
...
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p. 237.
p.000009: 30 CCMO Annual report 2010, p. 32.
p.000009: 31 See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”,
p.000009: Australian Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009:
p.000009: Final version
p.000010: 10
p.000010:
p.000010: As explained in the following point, the interest of the prior or prospective registration of clinical trials (phase
p.000010: II, III and IV trials32) is acknowledged on various sides. As regards the disclosure of information on phase I trials
p.000010: or first-into-man studies, however, there is more discussion.33
p.000010: Existing initiatives, points of view and guidelines
p.000010:
p.000010: There follows a non-exhaustive survey of a number of initiatives and points of view/guidelines
p.000010: concerning the prospective registration of research protocols. Some of these are covered in more detail in Annex 1.
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010: 32 The four successive phases of clinical trials are described in the introductory report to Opinion No 13 of 9 July
p.000010: 2001 on human experimentation, issued by the Committee, as follows (see point B. Definitions):
p.000010: “Phase I involves administering the product for the first time, in principle to a small number of volunteers in good
p.000010: health [editor’s note: often healthy volunteers, but not always, for example in the case of anti-cancer products], to
p.000010: assess their tolerance to the product, determine the maximum tolerated by humans and the minimum active dose of the
p.000010: product, and study its pharmacokinetic and pharmaco-dynamic properties.
p.000010: Phase II concerns trails on a limited group of patients suffering from the pathology for which the
p.000010: product is intended, in order to confirm its efficacy, assess its therapeutic interest, assess the relationship
p.000010: between the risks and the advantages linked to its administration and seek the best dose and the best
p.000010: means of administration depending n the effect sought.
p.000010: During phase III, studies are conducted on a large number of patients, usually divided into comparable
p.000010: groups, according to a strict methodology (randomisation). These studies aim to examine tolerance in the medium term
p.000010: and efficacy, so as to e able to estimate the relationship between the benefits and the disadvantages (unwanted effects
p.000010: and cost). This phase is also used to gather information which will be useful for prescribers. If it proves conclusive,
p.000010: the next step is to think about marketing the product and fulfilling the procedures to issue the authorisation to
p.000010: place it on the market.
p.000010: Phase IV comprises the studies conducted once the product has been put on the market. These studies are sued to gain
p.000010: better knowledge of the product: the possible association with other therapeutics, the discovery of new
p.000010: actions, the rare or belated side effects, etc.”
p.000010: 33 NIHR report 2010, p. 83.
...
p.000022: has been in force since 2009. According to this directive, the Dutch Central Commission for research
p.000022: involving human subjects (Centrale Commissie voor Mensgebonden Onderzoek, CCMO) gives medical-ethical assessment
p.000022: committees (METC) the tasks of checking whether protocols contain unreasonable restrictions as regards the
p.000022: publication of research findings.
p.000022:
p.000022: In this context, the Advisory Committee on Bioethics first sets out its general point of view regarding the
p.000022: publication of research findings. This is followed by a number of recommendations in response to
p.000022: the actual request for an opinion which has been reformulated as follows:
p.000022: When examining a protocol on human experimentation, can/must a medical ethics committee (MEC)
p.000022: check how the research findings – whether positive, negative or inconclusive – will be published or
p.000022: made publicly available?
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Final version
p.000023: 23
p.000023:
p.000023: 3.2. General point of view regarding the publication of research findings
p.000023: The Advisory Committee on Bioethics believes that as far as possible, the publication of all the findings of scientific
p.000023: research carried out on human subjects – whether they are positive, negative or inconclusive – is a matter of ethical
p.000023: duty.
p.000023:
p.000023: By taking part voluntarily in an experiment, the subjects who agree to undergo this – both healthy volunteers and
p.000023: patients – in fact contribute to the development of scientific knowledge, which is to benefit the entire
p.000023: community. Whatever the origin (community and/or other promoters) of the resources used for scientific
p.000023: research on humans, the findings of human experimentation must be made publicly available, if only
p.000023: because the experimentation is carried out on humans. Moreover, when the community provides the research
p.000023: resources, it goes without saying that it is also entitled to the publication of the research findings. The choices
p.000023: and decisions made in terms of the health economy are also based on scientific findings. Distorting these
p.000023: findings can lead to less suitable strategic decisions and therefore have consequences, in particular in
p.000023: economic terms (inadequate funding, wastage, etc.), for society as a whole.
p.000023:
p.000023: It should be pointed out here that the term ‘to make publicly available’ (‘openbaar maken’, ‘rendre public’) has a
p.000023: broader meaning that 'to publish’ ('publiceren'/'publier').
p.000023:
p.000023: 3.3. Recommendations
p.000023: a. Recommendation regarding the resources of medical ethics committees: a prior condition
p.000023: In this context, the Committee refers to the comment it made in the introductory report relating to
p.000023: opinion No 13 of 9 July 2001 on human experimentation, point E, 4, c, end of paragraph 2: “real means (secretariat,
p.000023: staff) must be allocated to existing ethics committees and a training programme must be gradually developed.”
p.000023:
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000006: trials and its influence on apparent efficacy”, New England Journal of Medicine 358, pp. 252-260.
p.000006: See also Doornbos B, de Jonge P, Bockting CLH. (2008), “Selectieve publicatie van onderzoek met antidepressiva:
p.000006: gevolgen voor de richtlijn ‘Depressie’”, Ned Tijdschr Geneeskd., 2008, 21 June, 152(25), pp. 1406-1408.
p.000006: 14 McGauran N, Wieseler B, Kreis J, Schüler Y-B, Kölsch H, Kaiser T. (2010), “Reporting bias in medical research – a
p.000006: narrative review”, Trials, 2010, 11:37, 15 p.
p.000006: See web page: www.trialsjournal.com/content/11/1/37
p.000006: This article includes a list of over 250 reference articles, some of which restate the references given in the NIHR
p.000006: report 2010.
p.000006:
p.000006: Final version
p.000007: 7
p.000007:
p.000007: were underreported, positive secondary outcomes were highlighted rather than negative primary outcomes15.
p.000007: Numerous studies have been conducted comparing publication bias. The NIHR report 2010 contains a list of 537
p.000007: reference articles. One of the objectives of the health technology assessment was in fact to identify
p.000007: and assess empirical studies on publication bias and related bias published as of 1998.
p.000007:
p.000007: It is also important that the outcome variables or the assessment criteria in the context of a clinical study are
p.000007: chosen carefully and that the limitations on variables or criteria are explained. Hochman et McCormick16
p.000007: thus stress that without any explanation of their limitations, the use of substitution criteria 17 or combined
p.000007: assessment criteria rather than clinical criteria, or of mortality due to illness rather than total mortality or the
p.000007: reporting of relative risks rather than absolute risks can lead to biased findings, which complicates the way they are
p.000007: interpreted by the doctors, the patients and the political decision-makers.
p.000007:
p.000007: An article by Lexchin et al.18 states that studies of medicinal products sponsored by pharmaceutical
p.000007: companies generate more positive research findings than the same studies on medicinal products conducted by
p.000007: researchers who are not working on behalf of the pharmaceutical industry.
p.000007: In his article, Steen19 indicates that 85 % of clinical trials sponsored by the industry result in positive findings,
p.000007: as against 50 % for studies financed by public funds. It is also possible that this is linked to the fact that the
p.000007: industry examines more advanced study phases when a positive outcome is more probable than in the initial phase
p.000007: of a research project.
p.000007:
p.000007: Need for adequate reporting
p.000007:
p.000007: It is important to report clinical trials adequately for both scientific and ethical reasons.20 Failing to publicly
p.000007: disclose findings that are ‘unfavourable’, ‘of no interest’, or not presenting sufficiently detailed
p.000007: findings (underreporting/selective reporting) can mean that patients are given treatment that is ineffective, or even
p.000007: harmful, for longer than is necessary or that they are refused a more effective treatment for longer than is
p.000007: necessary.21
p.000007:
p.000007:
p.000007:
p.000007: 15 First of all, the primary and secondary outcome variables defined in advance – that is prior to the execution of the
...
p.000009: presentation of scientific discoveries. Once this registration has been done, it is in fact possible to check
p.000009: later on whether the findings of a clinical trial have been published or publicly disclosed. It is also possible to
p.000009: detect whether the trial is still ongoing or has been prematurely interrupted and why. The reported research findings
p.000009: can also be compared with the research assumption or assumptions initially registered.26
p.000009: It should be noted that in the sixth version of the Declaration of Helsinki (Seoul, October 2008), a new Article
p.000009: 19 was inserted which expressly mentions the need for the prospective registration of clinical trials: (free
p.000009: translation)
p.000009: "Every clinical trial must be registered in a publicly accessible database before recruitment of the first
p.000009: subject."27
p.000009: In a working document28 from the World Health Organisation (WHO), the following advantages are
p.000009: associated with the prospective registration of clinical trials in public registers:
p.000009: - this registration is likely to be facilitate the recruitment of participants in clinical trials as it is
p.000009: also a means of informing potential participants and care providers of the existence of studies;29
p.000009: - the pointless duplication of a study already underway elsewhere can be avoided.
p.000009:
p.000009: The 2010 annual report from the Dutch Central Commission for research involving human subjects (Centrale Commissie
p.000009: voor Mensgebonden Onderzoek, CCMO) also stresses that patients are increasingly showing an interest in
p.000009: research relating to ‘their’ illness and sometimes seek specifically to take part in clinical trials
p.000009: through which they can access innovative treatments.30
p.000009: This transparency also enables promoters to deploy their resources in areas of study where there is still little
p.000009: evidence-based knowledge. Those who produce summaries of research findings, including the authors of systematic
p.000009: reviews, meta-analyses and practice guidelines, can thus efficiently and univocally identify all the trials that have
p.000009: been conducted or are still ongoing in their field of interest.31
p.000009:
p.000009:
p.000009: 26 Idem, see p. 414.
p.000009: See also NIHR report 2010, p. 53.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009: 27 Original version: “Every clinical trial must be registered in a publicly accessible database before recruitment of
p.000009: the first subject.”
p.000009: 28 Ghersi D, Clarke M, Berlin J, Gülmezoglu AM, Kush R, Lumbiganon P, Moher D, Rockhold F, Sim I, Wager
p.000009: E. (2008), “Reporting the findings of clinical trials: a discussion paper”, Bulletin of the World Health
p.000009: Organization, 86(6), pp. 492-493, see p. 492.
p.000009: See also Chalmers I, Altman DG. (1999), “How can medical journals help prevent poor medical research?
p.000009: Some opportunities presented by electronic publishing”, Lancet, vol. 353, pp. 490-493, see p. 491.
p.000009: 29 See also “WHO clinical trials initiative to protect the public”, Bulletin of the World Health Organization, January
p.000009: 2006, 84(1), pp. 10-11, see p. 11.
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000007: 21 See also NIHR report 2010, pp. 39-40.
p.000007:
p.000007: Final version
p.000008: 8
p.000008:
p.000008: Patients and healthy volunteers who take part in clinical trials make an important contribution
p.000008: to progress in scientific knowledge. Inadequate reporting and the non- publication of all the findings
p.000008: do not do justice to those who take part in trials voluntarily in a spirit of altruism.
p.000008: Another consequence of this may be that limited resources and funds are not used to best effect and are therefore
p.000008: wasted.
p.000008: Moreover, this jeopardises the integrity of scientific research. When striking research findings are more
p.000008: widely disseminated than inconclusive findings, this represents a threat to the validity of a research synopsis.22
p.000008: Which players are involved?
p.000008:
p.000008: The NIHR 2010 report stipulated that underreporting of research findings or a publication bias may result from a
p.000008: convergence of the interests of the researchers, peer reviewers, editors and sponsors, while at the same time
p.000008: pointing out that they may be responsible to differing degrees. Despite the fact that various complex
p.000008: factors play a role in the phenomenon of publication bias, the NIHR report states that it is possible
p.000008: to prevent publication bias to a certain extent and reduce its impact. The report puts forward measures to this end,
p.000008: including an adaptation of the policy on the publication of research findings, the possibility of electronic
p.000008: publication, an open access policy, the prospective registration of studies and the setting up of large-scale
p.000008: studies to confirm small-scale research findings.23
p.000008: The World Medical Association also sets out in Article 30 of the sixth version of the Declaration of
p.000008: Helsinki (Seoul, October 2008) a series of ethical obligations for the players concerned:
p.000008: "Authors, editors and publishers all have ethical obligations with regard to the publication of the results of
p.000008: research. Authors have a duty to make publicly available the results of their research on human subjects and are
p.000008: accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical
p.000008: reporting. Negative and inconclusive as well as positive results should be published or otherwise made
p.000008: publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in
p.000008: the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted
p.000008: for publication."24
p.000008: Iain Chalmers25 also stresses the responsibility of research ethics committees. These committees do but half
p.000008: their job when they approve a clinical trial, but do not then check whether the study is undertaken in line with the
p.000008: dossier submitted and whether the research findings have been adequately reported.
p.000008:
p.000008: On the basis of the NIHR report 2010, it may be concluded that the underreporting of research findings
...
p.000009: later on whether the findings of a clinical trial have been published or publicly disclosed. It is also possible to
p.000009: detect whether the trial is still ongoing or has been prematurely interrupted and why. The reported research findings
p.000009: can also be compared with the research assumption or assumptions initially registered.26
p.000009: It should be noted that in the sixth version of the Declaration of Helsinki (Seoul, October 2008), a new Article
p.000009: 19 was inserted which expressly mentions the need for the prospective registration of clinical trials: (free
p.000009: translation)
p.000009: "Every clinical trial must be registered in a publicly accessible database before recruitment of the first
p.000009: subject."27
p.000009: In a working document28 from the World Health Organisation (WHO), the following advantages are
p.000009: associated with the prospective registration of clinical trials in public registers:
p.000009: - this registration is likely to be facilitate the recruitment of participants in clinical trials as it is
p.000009: also a means of informing potential participants and care providers of the existence of studies;29
p.000009: - the pointless duplication of a study already underway elsewhere can be avoided.
p.000009:
p.000009: The 2010 annual report from the Dutch Central Commission for research involving human subjects (Centrale Commissie
p.000009: voor Mensgebonden Onderzoek, CCMO) also stresses that patients are increasingly showing an interest in
p.000009: research relating to ‘their’ illness and sometimes seek specifically to take part in clinical trials
p.000009: through which they can access innovative treatments.30
p.000009: This transparency also enables promoters to deploy their resources in areas of study where there is still little
p.000009: evidence-based knowledge. Those who produce summaries of research findings, including the authors of systematic
p.000009: reviews, meta-analyses and practice guidelines, can thus efficiently and univocally identify all the trials that have
p.000009: been conducted or are still ongoing in their field of interest.31
p.000009:
p.000009:
p.000009: 26 Idem, see p. 414.
p.000009: See also NIHR report 2010, p. 53.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009: 27 Original version: “Every clinical trial must be registered in a publicly accessible database before recruitment of
p.000009: the first subject.”
p.000009: 28 Ghersi D, Clarke M, Berlin J, Gülmezoglu AM, Kush R, Lumbiganon P, Moher D, Rockhold F, Sim I, Wager
p.000009: E. (2008), “Reporting the findings of clinical trials: a discussion paper”, Bulletin of the World Health
p.000009: Organization, 86(6), pp. 492-493, see p. 492.
p.000009: See also Chalmers I, Altman DG. (1999), “How can medical journals help prevent poor medical research?
p.000009: Some opportunities presented by electronic publishing”, Lancet, vol. 353, pp. 490-493, see p. 491.
p.000009: 29 See also “WHO clinical trials initiative to protect the public”, Bulletin of the World Health Organization, January
p.000009: 2006, 84(1), pp. 10-11, see p. 11.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
...
p.000013: ICMJE initiative that prospective registration is only effective if it is binding.
p.000013:
p.000013: 1.3. Publication of all research findings
p.000013: Meticulous prospective registration of clinical trials alone is not enough to guarantee the transparency
p.000013: of scientific research. Research findings must be and remain permanently accessible and should ideally be kept
p.000013: by an independent body.
p.000013:
p.000013: Ideally, all clinical trials should be recorded in public registers as soon as they start. All the research findings
p.000013: should then also be kept there. In fact, all new studies follow on from research carried out previously.
p.000013:
p.000013: The pharmaceutical industry acknowledges the interest of prior or prospective registration of clinical trials, but
p.000013: expresses reservations as to information that is sensitive in terms of competition46. As regards the
p.000013: publication of research findings, the pharmaceutical industry is more cautious, for the time being standing by the
p.000013: publication of findings from phase IV trials and, by extension, phase III trials. (See Annex 1, B.7.). The
p.000013: industry also stresses, rightly, the importance of protecting intellectual property rights and contract law.
p.000013: Premature communication of research findings, for example before a patent procedure has been settled, risks
p.000013: causing a company to lose a major competitive advantage.
p.000013:
p.000013: To achieve greater transparency in scientific research, Spielmans and Parry47 suggest in their article that
p.000013: better access to all raw research data should be promoted. The clinical trials registers in which protocols are
p.000013: registered in advance have not resolved the problem of underreporting or selective reporting. Publishers, peer
p.000013: reviewers, etc. should ideally check that the data published correspond to the ‘raw’ research findings and the protocol
p.000013: registered beforehand. The reports which are forwarded to regulatory bodies such as the FDA should
p.000013:
p.000013:
p.000013: 43 Viergever RF, Ghersi D. (2011), “The quality of registration of clinical trials”, PLoS ONE, February
p.000013: 2011 6(2), e14701, pp. 1-8 – web page:
p.000013: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014701 44 NIHR report 2010, p. 83.
p.000013: 45 NIHR report 2010, p. 56.
p.000013: 46 See annexe 1, B.2.: The pharmaceutical industry puts forward objections to the prospective publication
p.000013: of information in information fields 10, 13, 17, 19 and 20, but the WHO stands by to the prospective registration and
p.000013: publication of all these points. The fields of information in question are: 10. Scientific Title - 13. Intervention(s)
p.000013: - 17. Target Sample Size - 19. Primary Outcome(s) - 20. Key Secondary Outcomes.
p.000013: 47 Spielmans GI, Parry PI. (2010), “From evidence-based medicine to marketing-based medicine: evidence
p.000013: from internal industry documents”. Journal of Bioethical Inquiry, Springer, 2010( 7), pp. 13-29 – see web
p.000013: page: i.bnet.com/blogs/spielmans-parry-ebm-to-mbm-jbioethicinqu-2010.pdf
p.000013:
p.000013: Final version
p.000014: 14
p.000014:
p.000014: also be made public as discrepancies are often observed between the data reported there et those published in
p.000014: medical-scientific reviews.48
p.000014: Not only pharmaceutical companies, but also editors have commercial interests that need to be balanced against the
p.000014: advantages of broad access to precise data for science. Thus editors, too, wish to be able to control the
p.000014: dissemination of research findings (see Annex 1, B.4., not. Ingelfinger rule) and they point to the need for peer
p.000014: reviews49 to guarantee quality. Moreover, they also favour the publication of clinical trials accompanied by
p.000014: ‘positive’ findings50.
p.000014: Spielmans and Parry refer in their article to a possible solution devised by Richard Smith, a former editor of the
p.000014: British Medical Journal. His proposal consists of publishing the protocols of studies and their findings
p.000014: in an online register only, and publishing solely articles that discuss the validity of these studies in
p.000014: scientific periodicals. This may seem to be a curious solution, but according to the two authors, it has not really
p.000014: been proved that peer review results in clearly better reporting of research findings.51
p.000014: In this context, the NIHR report 2010 points out that electronic publication offers the possibility of
p.000014: unlimited publication space so that more information and data could be made accessible. Studies could thus be judged on
p.000014: their design and methodology, as well as the immediate relevance of findings in practice. The editors of
p.000014: electronic reviews could also encourage the publication of studies with negative or inconclusive findings. 52
p.000014: Finally, it may be asserted that transparency is also essential to detect scientific fraud, such as deliberately
p.000014: holding back negative findings or the distortion of research data.
p.000014:
p.000014: Existing initiatives, points of view and existing guidelines
p.000014:
p.000014: There also follows a non-exhaustive survey of a certain number of initiatives and existing points of
...
p.000016: des Lettres et des Beaux Arts de Belgique, the Academie Royale de Médecine de Belgique, the Koninklijke
p.000016: Vlaamse Academie van België voor Wetenschappen en Kunsten and the Koninklijke Academie voor Geneeskunde van België,
p.000016: supported by the SPP Politique scientifique. This code sets out the main principles of ethically justified scientific
p.000016: practice.
p.000016:
p.000016: European scientific organisations also stress the need to make publicly available all the findings of
p.000016: clinical trials and to this end, to develop integrated databases for clinical research. (See Annex 1, B.5 et
p.000016: B.6).
p.000016:
p.000016: The CONSORT group is an international network which includes researchers (trialists), methodologists and
p.000016: editors of specialised medical reviews. This group has drawn up a declaration – the most recent CONSORT
p.000016: statement dated from 2010 – setting out a minimum set of evidence-based recommendations for the reporting of randomised
p.000016: clinical trials (RCTs) (www.consort-statement.org).
p.000016:
p.000016: The EQUATOR project also grew out of this group in 2006. It aims to improve the reliability and value of medical
p.000016: research literature by promoting the transparent and precise reporting of studies. The EQUATOR network was
p.000016: officially inaugurated in London in 2008 (www.equator-network.org). This umbrella organisation includes
p.000016: researchers, editors of specialised medical reviews, peer reviewers, developers of reporting guidelines,
p.000016: research funding bodies, in short everyone who has an interest in improving the quality of research and research
p.000016: publications.
p.000016:
p.000016: It is also worth noting that in 2002, the open access peer-reviewed online Journal of Negative Findings
p.000016: in Biomedicine, was introduced.60
p.000016: Some conclusions
p.000016:
p.000016: Many bodies see the interest of making all research findings accessible: not only generally ‘positive’ findings which
p.000016: are published in scientific reviews, but also inconclusive or negative findings, or all ‘raw’ research findings
p.000016: (raw data). Complete transparency of scientific discoveries also proves necessary to promote medicine that is
p.000016: truly evidence based. Given this interest, however, it is also necessary to take account of the real
p.000016: commercial and economic interests of the pharmaceutical industry, in particular. Nevertheless, more and more
p.000016: initiatives are being taken that aim to achieve complete transparency in research findings.
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016: 58 For more details, see point 1.1. Underreporting of research results – Who is involved? 59 See
p.000016: www.belspo.be/belspo/organisation/publ/Eth_code_fr.stm
p.000016: 60 NIHR report 2010, p. 53.
p.000016: See also web page: www.jnrbm.com: “Journal of Negative Results in BioMedicine is an open access, peer-reviewed, online
p.000016: journal that promotes a discussion of unexpected, controversial, provocative and/or negative results in the context of
p.000016: current tenets.”
p.000016:
p.000016: Final version
p.000017: 17
p.000017:
p.000017: 2. ROLE OF MEDICAL ETHICS COMMITTEES
p.000017: In the context of the ethical examination of a protocol on human experimentation, can/must a medical ethics
p.000017: committee check in what way the research findings – whether positive, negative or inconclusive – will be
p.000017: published or made publicly available? This is the request for an opinion as reformulated by the Committee.
p.000017:
p.000017: The Council of Europe and the Dutch Central Commission for research involving human subjects (Centrale
p.000017: Commissie voor Mensgebonden Onderzoek, CCMO) have recently considered this question.
p.000017:
p.000017:
p.000017: 2.1. Guide from the Council of Europe intended for Research Ethics Committees (REC) 61
p.000017: On 7 February 2011, the Council of Europe published a guide intended for the members of research ethics committees
p.000017: (REC). Article 28 of the additional protocol to the Oviedo Convention on Human Rights and Biomedicine relating
p.000017: to biomedical research already states that when a research project is over, a report or a summary should
p.000017: be drawn up to be forwarded to the medical ethics committee or the competent authorities.
p.000017:
p.000017: The guide refers above all to interventional studies carried out on human subjects. However, it may be supposed that
p.000017: some points, such as access to research findings, are relevant for all biomedical and scientific research projects in
p.000017: which human subjects are involved.62
p.000017: The guide distinguishes three research stages63. Below, some of the recommendations in the guide are briefly
p.000017: compared with the provisions in European Directive 2001/20/EC on interventional studies involving medicinal
p.000017: products and the Belgian act of 7 May 2004 on human experimentation64.
p.000017: a. Before the research starts
p.000017: The guide states that the RECs should assess the ethical acceptability of biomedical research projects (‘their main
p.000017: objective’).
p.000017:
p.000017: b. During the research
p.000017: According to the guide, the RECs should follow up the research projects they have approved and may need to re-examine
p.000017: them owing to new and relevant knowledge acquired during the research.
p.000017:
p.000017: c. After the research
p.000017: The guide states that the role of the REC in this stage is still fairly limited:
p.000017: “The role of the REC, once the research is over, is currently limited […]. It is generally considered
p.000017: that this is not the period when recourse to the expertise of the REC is the most important. Moreover, the RECs
p.000017: rarely have the legal competence, the time and other resources to work effectively to this end.”
p.000017:
p.000017: However, the guide states that the RECs should also check whether a transparent report has been drawn up on the results
p.000017: of the research projects they have examined:
p.000017:
p.000017:
p.000017:
p.000017: 61 See also annexe 1, B.3. and web page: www.coe.int/t/dg3/healthbioethic/source/INF(2011)_fr.pdf
...
p.000018: with medicinal products (FAMHP) or the participants in the trial.
p.000018:
p.000018: As we have already mentioned, a draft text from the European Commission proposes that in future, the findings of
p.000018: clinical trials should be made publicly available via the Clinical Trials Register at the latest twelve months after
p.000018: the end of the trial – whether it was completed or interrupted prematurely. For paediatric trials, this, this
p.000018: period of time is reduced to six months. (See Annex 1, A.2.).
p.000018:
p.000018: - publication of research findings for scientific and health-care purposes: (extract from the Council of Europe
p.000018: guide)
p.000018:
p.000018:
p.000018:
p.000018:
p.000018: Final version
p.000019: 19
p.000019:
p.000019: “lt is important to make research findings publicly available, irrespective of whether the research
p.000019: assumption has been confirmed (positive result) or invalidated (negative result) or these findings do not
p.000019: lead to a conclusion.” […] The additional protocol to the Oviedo Convention on biomedical research makes it mandatory
p.000019: for researchers to submit a report or a summary to the REC at the end of the study. Should study end prematurely, a
p.000019: report including the reasons for this should also be submitted to the REC. Moreover, the protocol requires the
p.000019: publication of findings within a reasonable period of time, as well as the communication of the
p.000019: conclusions of the research to participants who so request. The REC must therefore have access to elements
p.000019: enabling it to ensure that the researchers have defined a publication policy, that they have discussed the matter
p.000019: with all external promoters so that they are not prevented from publishing the findings owing to contractual
p.000019: obligations. A reasonable period of time for publication is acceptable, in not order to adversely affect a
p.000019: patent application. However, this argument should not constitute a pretext for the unlimited retention of the
p.000019: findings.
p.000019: Particular concerns have been expressed regarding the publication of research findings on potential new
p.000019: treatments, biased notably owing to the concealment of ‘unfavourable’ findings. To overcome this practice and
p.000019: ensure that the findings are published, researchers should register all research projects before they begin in a
p.000019: register that is accessible to the public. The members of the REC can encourage this effort at transparency by making
p.000019: this registration a condition for their positive opinion regarding the ethical acceptability of the research
p.000019: project. Although national legislation does not allow the opinion to be conditioned by a request
p.000019: like this, the REC should at least use its position to request that all the findings be made publicly
p.000019: available.”
p.000019:
p.000019: Neither European Directive 2001/20/EC nor the Belgian law of 7 May 2004 expressly mentions that a
p.000019: medical ethics committee is competent to monitor the publication policy adopted for a research project. In the
p.000019: Netherlands, this provision is, however, made.
...
Searching for indicator access to information:
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p.000012: ethical topics they have covered. On the basis of these data, the Advisory Committee on Bioethics draws up an annual
p.000012: report on the activities of the MECs. This a posteriori report only includes approved data.
p.000012:
p.000012: As regards experiments that fall under the Belgian act but are not interventional clinical studies with
p.000012: medicinal products as referred to in European Directive 2001/20/EC38, a unique Belgian number has to be requested in
p.000012: advance on a website run by the Federal Agency for Medicines and Health Products (FAMHP).
p.000012:
p.000012: Interventional clinical studies on medicinal products referred to by the European directive39 must be prospectively
p.000012: recorded in the EudraCT database, in which a number of information fields are open for public consultation via the
p.000012: Clinical Trials Register.
p.000012:
p.000012: It should be stressed that a project is underway within the FAMHP with a view to developing an interactive website40
p.000012: for the registration and follow-up of clinical trials.
p.000012: The editors (ICMJE)
p.000012:
p.000012: A major initiative has also been taken in the world of publishing. Further to the decision of the International
p.000012: Committee of Medical Journal Editors (ICMJE), in 2004, to henceforth accept for publication only clinical trials
p.000012: that have undergone prospective registration41 in a recognised public register, an increase of over 70 % in the
p.000012: number of clinical trials registered was observed in 2005.42 (See also Annex 1, B.4.).
p.000012: The pharmaceutical industry (IFPMA)
p.000012:
p.000012: The pharmaceutical industry acknowledges the interest of granting health-care providers, patients and others
p.000012: access to information on clinical trials while stressing the need to take account, when disclosing such
p.000012: information, of privacy, intellectual property rights and contract law. (See also Annex 1, B.7.).
p.000012:
p.000012: Some observations
p.000012:
p.000012: Prospective registration can only contribute toward greater transparency in scientific research when
p.000012: the data are registered in full and are, moreover, significant. A study conducted on 5 % of the clinical
p.000012: trials registered prospectively between, June 2008 and June 2009 in a register that is part of the WHO
p.000012: International Clinical Trials Registry Platform
p.000012:
p.000012: 38 In other words, all experimentation falling under the application of the Belgian act of 7 May 2004 on human
p.000012: experimentations, to the exclusion of clinical trials.
p.000012: 39 In other words, clinical trials as defined in the Belgian act of 7 May 2004 on human experimentation.
p.000012: 40 See also Circular No 512 from the FAMHP (2008), point 3: “The interactive website is intended to
p.000012: improve communication between the various parties involved for the approval of an experiment (promoter –
p.000012: lead ethics committee – local ethics committee – FAMPH).” – see website:
p.000012: www.fagg-afmps.be/fr/items/circulaires/2002-2008/
p.000012: 41 Both the ICMJE and the WHO define prospective registration as the recording of the clinical trial in a register
p.000012: before the recruitment of the first person involved in the research.
p.000012: 42 NIHR report 2010, p. 54 [with reference to Zarin DA, Tse T, Ide NC. (2005), “Trial registration at
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000008: The World Medical Association also sets out in Article 30 of the sixth version of the Declaration of
p.000008: Helsinki (Seoul, October 2008) a series of ethical obligations for the players concerned:
p.000008: "Authors, editors and publishers all have ethical obligations with regard to the publication of the results of
p.000008: research. Authors have a duty to make publicly available the results of their research on human subjects and are
p.000008: accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical
p.000008: reporting. Negative and inconclusive as well as positive results should be published or otherwise made
p.000008: publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in
p.000008: the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted
p.000008: for publication."24
p.000008: Iain Chalmers25 also stresses the responsibility of research ethics committees. These committees do but half
p.000008: their job when they approve a clinical trial, but do not then check whether the study is undertaken in line with the
p.000008: dossier submitted and whether the research findings have been adequately reported.
p.000008:
p.000008: On the basis of the NIHR report 2010, it may be concluded that the underreporting of research findings
p.000008: is a complex problem, which is important given the impact it exerts on the integrity of scientific research. Many
p.000008: articles as well as the NIHR report single out the need to
p.000008:
p.000008: See also Sandercock P. (2011 copyright) “Negative results: why do they need to be published?”, International Journal of
p.000008: Stroke, Vol 7, January 2012, pp. 32-33, see p. 32.
p.000008: See web page: onlinelibrary.wiley.com/doi/10.1111/j.1747-4949.2011.00723.x/full. 22 NIHR report 2010, p. X.
p.000008: 23 NIHR report 2010, p. 50-51.
p.000008: 24 Original version: “Authors, editors and publishers all have ethical obligations with regard to the publication of
p.000008: the results of research. Authors have a duty to make publicly available the results of their research
p.000008: on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to
p.000008: accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be
p.000008: published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of
p.000008: interest should be declared in the publication. Reports of research not in accordance with the principles of this
p.000008: Declaration should not be accepted for publication.”
p.000008: 25 Chalmers I. “Underreporting research is scientific misconduct”, abridged version in Ethical and
p.000008: regulatory aspects of clinical research: readings and commentary, Ezekiel JE et al., Johns Hopkins University Press,
p.000008: 2003, pp. 411-414 , see pp. 413-414.
p.000008:
p.000008: Final version
p.000009: 9
p.000009:
p.000009: (1) register the protocol data in public registers (including the definition of primary outcomes) in
p.000009: advance and (2) make all research findings accessible.
p.000009:
p.000009: 1.2. Prospective registration in a public register
p.000009: The registration of clinical trials in a public register before they begin is a first step that make it
...
Social / Occupation
Searching for indicator job:
(return to top)
p.000008: to prevent publication bias to a certain extent and reduce its impact. The report puts forward measures to this end,
p.000008: including an adaptation of the policy on the publication of research findings, the possibility of electronic
p.000008: publication, an open access policy, the prospective registration of studies and the setting up of large-scale
p.000008: studies to confirm small-scale research findings.23
p.000008: The World Medical Association also sets out in Article 30 of the sixth version of the Declaration of
p.000008: Helsinki (Seoul, October 2008) a series of ethical obligations for the players concerned:
p.000008: "Authors, editors and publishers all have ethical obligations with regard to the publication of the results of
p.000008: research. Authors have a duty to make publicly available the results of their research on human subjects and are
p.000008: accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical
p.000008: reporting. Negative and inconclusive as well as positive results should be published or otherwise made
p.000008: publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in
p.000008: the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted
p.000008: for publication."24
p.000008: Iain Chalmers25 also stresses the responsibility of research ethics committees. These committees do but half
p.000008: their job when they approve a clinical trial, but do not then check whether the study is undertaken in line with the
p.000008: dossier submitted and whether the research findings have been adequately reported.
p.000008:
p.000008: On the basis of the NIHR report 2010, it may be concluded that the underreporting of research findings
p.000008: is a complex problem, which is important given the impact it exerts on the integrity of scientific research. Many
p.000008: articles as well as the NIHR report single out the need to
p.000008:
p.000008: See also Sandercock P. (2011 copyright) “Negative results: why do they need to be published?”, International Journal of
p.000008: Stroke, Vol 7, January 2012, pp. 32-33, see p. 32.
p.000008: See web page: onlinelibrary.wiley.com/doi/10.1111/j.1747-4949.2011.00723.x/full. 22 NIHR report 2010, p. X.
p.000008: 23 NIHR report 2010, p. 50-51.
p.000008: 24 Original version: “Authors, editors and publishers all have ethical obligations with regard to the publication of
p.000008: the results of research. Authors have a duty to make publicly available the results of their research
p.000008: on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to
p.000008: accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be
p.000008: published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of
p.000008: interest should be declared in the publication. Reports of research not in accordance with the principles of this
p.000008: Declaration should not be accepted for publication.”
p.000008: 25 Chalmers I. “Underreporting research is scientific misconduct”, abridged version in Ethical and
...
Social / Property Ownership
Searching for indicator property:
(return to top)
p.000012:
p.000012: As regards experiments that fall under the Belgian act but are not interventional clinical studies with
p.000012: medicinal products as referred to in European Directive 2001/20/EC38, a unique Belgian number has to be requested in
p.000012: advance on a website run by the Federal Agency for Medicines and Health Products (FAMHP).
p.000012:
p.000012: Interventional clinical studies on medicinal products referred to by the European directive39 must be prospectively
p.000012: recorded in the EudraCT database, in which a number of information fields are open for public consultation via the
p.000012: Clinical Trials Register.
p.000012:
p.000012: It should be stressed that a project is underway within the FAMHP with a view to developing an interactive website40
p.000012: for the registration and follow-up of clinical trials.
p.000012: The editors (ICMJE)
p.000012:
p.000012: A major initiative has also been taken in the world of publishing. Further to the decision of the International
p.000012: Committee of Medical Journal Editors (ICMJE), in 2004, to henceforth accept for publication only clinical trials
p.000012: that have undergone prospective registration41 in a recognised public register, an increase of over 70 % in the
p.000012: number of clinical trials registered was observed in 2005.42 (See also Annex 1, B.4.).
p.000012: The pharmaceutical industry (IFPMA)
p.000012:
p.000012: The pharmaceutical industry acknowledges the interest of granting health-care providers, patients and others
p.000012: access to information on clinical trials while stressing the need to take account, when disclosing such
p.000012: information, of privacy, intellectual property rights and contract law. (See also Annex 1, B.7.).
p.000012:
p.000012: Some observations
p.000012:
p.000012: Prospective registration can only contribute toward greater transparency in scientific research when
p.000012: the data are registered in full and are, moreover, significant. A study conducted on 5 % of the clinical
p.000012: trials registered prospectively between, June 2008 and June 2009 in a register that is part of the WHO
p.000012: International Clinical Trials Registry Platform
p.000012:
p.000012: 38 In other words, all experimentation falling under the application of the Belgian act of 7 May 2004 on human
p.000012: experimentations, to the exclusion of clinical trials.
p.000012: 39 In other words, clinical trials as defined in the Belgian act of 7 May 2004 on human experimentation.
p.000012: 40 See also Circular No 512 from the FAMHP (2008), point 3: “The interactive website is intended to
p.000012: improve communication between the various parties involved for the approval of an experiment (promoter –
p.000012: lead ethics committee – local ethics committee – FAMPH).” – see website:
p.000012: www.fagg-afmps.be/fr/items/circulaires/2002-2008/
p.000012: 41 Both the ICMJE and the WHO define prospective registration as the recording of the clinical trial in a register
p.000012: before the recruitment of the first person involved in the research.
p.000012: 42 NIHR report 2010, p. 54 [with reference to Zarin DA, Tse T, Ide NC. (2005), “Trial registration at
p.000012: ClinicalTrials.gov between May and October 2005”, N Engl J Med 2005; 353:2779987].
p.000012:
p.000012: Final version
p.000013: 13
p.000013:
...
p.000013: An initial, essential stage to prevent underreporting or a publication bias as regards research findings consists of
p.000013: moving towards worldwide prospective registration of clinical trials – in their broadest definition and including
p.000013: basic research. This registration will only really be able to contribute towards greater transparency if
p.000013: the data registered are complete and significant, and they are also kept up to date. It further emerges from the
p.000013: ICMJE initiative that prospective registration is only effective if it is binding.
p.000013:
p.000013: 1.3. Publication of all research findings
p.000013: Meticulous prospective registration of clinical trials alone is not enough to guarantee the transparency
p.000013: of scientific research. Research findings must be and remain permanently accessible and should ideally be kept
p.000013: by an independent body.
p.000013:
p.000013: Ideally, all clinical trials should be recorded in public registers as soon as they start. All the research findings
p.000013: should then also be kept there. In fact, all new studies follow on from research carried out previously.
p.000013:
p.000013: The pharmaceutical industry acknowledges the interest of prior or prospective registration of clinical trials, but
p.000013: expresses reservations as to information that is sensitive in terms of competition46. As regards the
p.000013: publication of research findings, the pharmaceutical industry is more cautious, for the time being standing by the
p.000013: publication of findings from phase IV trials and, by extension, phase III trials. (See Annex 1, B.7.). The
p.000013: industry also stresses, rightly, the importance of protecting intellectual property rights and contract law.
p.000013: Premature communication of research findings, for example before a patent procedure has been settled, risks
p.000013: causing a company to lose a major competitive advantage.
p.000013:
p.000013: To achieve greater transparency in scientific research, Spielmans and Parry47 suggest in their article that
p.000013: better access to all raw research data should be promoted. The clinical trials registers in which protocols are
p.000013: registered in advance have not resolved the problem of underreporting or selective reporting. Publishers, peer
p.000013: reviewers, etc. should ideally check that the data published correspond to the ‘raw’ research findings and the protocol
p.000013: registered beforehand. The reports which are forwarded to regulatory bodies such as the FDA should
p.000013:
p.000013:
p.000013: 43 Viergever RF, Ghersi D. (2011), “The quality of registration of clinical trials”, PLoS ONE, February
p.000013: 2011 6(2), e14701, pp. 1-8 – web page:
p.000013: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014701 44 NIHR report 2010, p. 83.
p.000013: 45 NIHR report 2010, p. 56.
p.000013: 46 See annexe 1, B.2.: The pharmaceutical industry puts forward objections to the prospective publication
p.000013: of information in information fields 10, 13, 17, 19 and 20, but the WHO stands by to the prospective registration and
p.000013: publication of all these points. The fields of information in question are: 10. Scientific Title - 13. Intervention(s)
p.000013: - 17. Target Sample Size - 19. Primary Outcome(s) - 20. Key Secondary Outcomes.
p.000013: 47 Spielmans GI, Parry PI. (2010), “From evidence-based medicine to marketing-based medicine: evidence
...
p.000021: “De richtlijn beoogt het bewaken van het belang van openbaarmaking van de onderzoeksresultaten en het
p.000021: voorkomen van voortijdige beëindiging van onderzoek om niet-medisch-wetenschappelijke redenen. Dit kan immers tot
p.000021: gevolg hebben dat tot dan toe geïncludeerde proefpersonen voor niets hebben deelgenomen aan een klinisch
p.000021: onderzoek.”
p.000021: 68 CCMO annual report 2010: summary p. 6.
p.000021:
p.000021: Final version
p.000022: 22
p.000022:
p.000022: 3. GENERAL POINT OF VIEW AND RECOMMENDATIONS
p.000022: 3.1. Context
p.000022: Publication bias or the underreporting of research findings – especially those that are negative – is a
p.000022: complex problem that involves various stakeholders.
p.000022: Several initiatives have been developed over the past decade that aim to promote the transparency and
p.000022: hence the integrity of scientific research.
p.000022: The public registers used for the prospective registration of protocols offer the possibility of following up the
p.000022: implementation of clinical trials and observing/researching the findings. The pharmaceutical industry is
p.000022: admittedly reluctant to communicate information from protocols concerning the early phases of research. This may,
p.000022: indeed, be information that is sensitive in terms of competition.
p.000022: Adequate prospective registration in public registers alone is not enough to guarantee the transparency of scientific
p.000022: research. Research findings must also be made accessible. The pharmaceutical industry also supports
p.000022: transparency, while stressing the need to protect intellectual property rights, contract law, etc.
p.000022: Here in Belgium, there are not as yet any public registers for the prospective registration of protocols. We should
p.000022: stress, however, that all interventional clinical studies with medicinal products have to be registered in the
p.000022: European EudraCT database before they begin. Since the start of 2011, some of the information from this
p.000022: database has been open for public consultation via the Clinical Trial Register or
p.000022: https://www.clinicaltrialsregister.eu. The research findings themselves are not yet included in the European database,
p.000022: but as a draft text from the European Commission reveals, the aim is indeed to register findings here as well in the
p.000022: future. In this respect, the European Medicines Agency (EMA) is following, with some delay, the initiatives taken by
p.000022: the American FDA which, since 2007, has registered all findings in the public register www.clinicaltrials.gov.
p.000022:
p.000022: As regards medical ethics committees, the Council of Europe guide (2010) for the members of research ethics committees,
p.000022: makes the following recommendations: once their research is complete, researchers must (1) forward a report or a
p.000022: synopsis of their conclusions to the medical ethics committee which initially assessed the research, and (2)
p.000022: confirm their initial proposals concerning the publication of findings in scientific journals or their
p.000022: public communication by other means. In order to thwart the publication of biased research findings, it is
p.000022: recommended that ethical approval by the ethical committees be made subject to prospective registration of the protocol
...
Social / Threat of Stigma
Searching for indicator threat:
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p.000007: aspects of clinical research: readings and commentary, Ezekiel, J.E. et al., Johns Hopkins University Press, 2003, pp.
p.000007: 411-414, see p. 411-412. [The article was initially published in JAMA 263 (1990), pp.1405-1408]
p.000007: See also NIHR report 2010, p. X.
p.000007: See also Rennie D. (2008), “The obligation to publish and disseminate results”, in The Oxford textbook of clinical
p.000007: research ethics, Ezekiel JE et al., Oxford University Press, pp. 795-807, see p. 795.
p.000007: See also Strech D. (2012), “Normative arguments and new solutions for the unbiased registration and publication of
p.000007: clinical trials”, Journal of Clinical Epidemiology (Elsevier), 65 (2012) pp. 279-281 [Epub 2011 Oct 18/19] – web page:
p.000007: www.open-project.eu/publications.
p.000007: 21 See also NIHR report 2010, pp. 39-40.
p.000007:
p.000007: Final version
p.000008: 8
p.000008:
p.000008: Patients and healthy volunteers who take part in clinical trials make an important contribution
p.000008: to progress in scientific knowledge. Inadequate reporting and the non- publication of all the findings
p.000008: do not do justice to those who take part in trials voluntarily in a spirit of altruism.
p.000008: Another consequence of this may be that limited resources and funds are not used to best effect and are therefore
p.000008: wasted.
p.000008: Moreover, this jeopardises the integrity of scientific research. When striking research findings are more
p.000008: widely disseminated than inconclusive findings, this represents a threat to the validity of a research synopsis.22
p.000008: Which players are involved?
p.000008:
p.000008: The NIHR 2010 report stipulated that underreporting of research findings or a publication bias may result from a
p.000008: convergence of the interests of the researchers, peer reviewers, editors and sponsors, while at the same time
p.000008: pointing out that they may be responsible to differing degrees. Despite the fact that various complex
p.000008: factors play a role in the phenomenon of publication bias, the NIHR report states that it is possible
p.000008: to prevent publication bias to a certain extent and reduce its impact. The report puts forward measures to this end,
p.000008: including an adaptation of the policy on the publication of research findings, the possibility of electronic
p.000008: publication, an open access policy, the prospective registration of studies and the setting up of large-scale
p.000008: studies to confirm small-scale research findings.23
p.000008: The World Medical Association also sets out in Article 30 of the sixth version of the Declaration of
p.000008: Helsinki (Seoul, October 2008) a series of ethical obligations for the players concerned:
p.000008: "Authors, editors and publishers all have ethical obligations with regard to the publication of the results of
p.000008: research. Authors have a duty to make publicly available the results of their research on human subjects and are
p.000008: accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical
p.000008: reporting. Negative and inconclusive as well as positive results should be published or otherwise made
...
Social / Trade Union Membership
Searching for indicator union:
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p.000010: product, and study its pharmacokinetic and pharmaco-dynamic properties.
p.000010: Phase II concerns trails on a limited group of patients suffering from the pathology for which the
p.000010: product is intended, in order to confirm its efficacy, assess its therapeutic interest, assess the relationship
p.000010: between the risks and the advantages linked to its administration and seek the best dose and the best
p.000010: means of administration depending n the effect sought.
p.000010: During phase III, studies are conducted on a large number of patients, usually divided into comparable
p.000010: groups, according to a strict methodology (randomisation). These studies aim to examine tolerance in the medium term
p.000010: and efficacy, so as to e able to estimate the relationship between the benefits and the disadvantages (unwanted effects
p.000010: and cost). This phase is also used to gather information which will be useful for prescribers. If it proves conclusive,
p.000010: the next step is to think about marketing the product and fulfilling the procedures to issue the authorisation to
p.000010: place it on the market.
p.000010: Phase IV comprises the studies conducted once the product has been put on the market. These studies are sued to gain
p.000010: better knowledge of the product: the possible association with other therapeutics, the discovery of new
p.000010: actions, the rare or belated side effects, etc.”
p.000010: 33 NIHR report 2010, p. 83.
p.000010: See also Annex 3, point 3. Scope of application: “The information to be included in the EudraPharm database further to
p.000010: section 4 covers clinical trials, phases II, III et IV, (…).”
p.000010:
p.000010: Final version
p.000011: 11
p.000011:
p.000011: The European Union (EMA)
p.000011:
p.000011: Protocols on interventional clinical trials with medicinal products that fall under the scope of application of
p.000011: European Directive 2001/20/EC, must be registered prospectively in the EudraCT database. In early 2011, the
p.000011: Clinical Trials Register34 was launched in which the European Medicines Agency (EMA) makes public several field of
p.000011: information in the EudraCT database. The European Commission describes the interest of this procedure as follows:
p.000011: “This information is potentially useful for patients, care staff and the health professionals, who may be
p.000011: interested in the trials that are underway and trials that have already been carried out. Moreover, more transparent
p.000011: information can contribute towards the development of research and thus guarantee the devising of better quality
p.000011: trials, requiring the participation of a smaller number of patients and avoiding all needless duplication. The
p.000011: pharmaceutical industry, university and scientific circles as well as the regulatory bodies are other potential users
p.000011: of this type of information.”35
p.000011: The United States (FDA)
p.000011:
p.000011: In the United States, since February 2000 there has been a similar public register at the Food and Drug
p.000011: Administration (FDA) where clinical trials are recorded before they begin, see www.clinicaltrials.gov.
p.000011:
p.000011: The World Health Organisation (WHO)
p.000011:
p.000011: The World Health Organisation is also endeavouring, with its International Clinical Trials Registry
p.000011: Platform (ICTRP) to produce a comprehensive list of clinical trials with a view to guaranteeing greater
...
p.000014: 51 Idem, see p. 26 [with reference to Jefferson T, Rudin M, Brodney Folse S, Davidoff F. (2007) “Editorial peer review
p.000014: for improving the quality of reports of biomedical studies”, Cochrane Database of Systematic Reviews 2].
p.000014: 52 NIHR report 2010, pp. 52-53.
p.000014: See also Chalmers I. “Underreporting research is scientific misconduct, abridged version in Ethical and regulatory
p.000014: aspects of clinical research: readings and commentary, Ezekiel JE et al., Johns Hopkins University Press 2003, pp.
p.000014: 411-414, see pp. 413-414.
p.000014: See also Sandercock P. (2011 copyright) “Negative results: why do they need to be published?”, International Journal of
p.000014: Stroke, Vol. 7, January 2012, pp. 32-33, see p. 33.
p.000014: Web page: onlinelibrary.wiley.com/doi/10.1111/j.1747-4949.2011.00723.x/full.
p.000014: 53 “US commission recommends increased protection for people in research after reviewing 1940s syphilis study”,
p.000014: BMJ 2011; 343.d5577 (published 2 September 2011) – original version:
p.000014: “Greater transparency and monitoring of research are needed to hold investigator and institutions responsible and
p.000014: accountable for violations of rules, standards and practices.
p.000014:
p.000014: Final version
p.000015: 15
p.000015:
p.000015: that the states should think about making the registration of all research studies comprising a more than minimal risk
p.000015: and the publication of their findings mandatory. Similarly, greater transparency and closer control of research are
p.000015: needed to be able to make researchers and research institutions responsible for the infringement of rules, standards,
p.000015: etc.
p.000015:
p.000015: The European Union (EMA)
p.000015:
p.000015: As also mentioned above, on 22 March 2011, the European Medicines Agency (EMA) launched the Clinical
p.000015: Trials Register (https://www.clinicaltrialsregister.eu) in which information fields from protocols that
p.000015: have been prospectively registered in the EudraCT database are published. Public consultation of the findings of
p.000015: all clinical trials registered is not yet possible at the moment, but according to a draft text from the European
p.000015: Commission dated 1 June 201054 which has been submitted for public consultation, this is the aim55. For clinical
p.000015: trials, the proposal is for the findings to be sent to the EMA at the latest twelve months after the
p.000015: end of the trial – whether this ended as planned or was interrupted prematurely – so that the EMA can
p.000015: include the findings in the EudraCT database. For paediatric trials, this period is reduced to six months. The
p.000015: findings should also be accessible to the public via the Clinical Trials Register within five working days after a
p.000015: validated data set has been sent to the EMA (see below, Annex 1, A.2.).
p.000015:
p.000015: The OPEN project jointly funded by the European Commission (7th framework programme) was started up at the end of
p.000015: 2011. This two-year project ran from 1 November 2011 to 31 October 2013. Its main aim was to examine
p.000015: the possibilities of overcoming the underreporting of negative findings (to Overcome the failure to Publish
p.000015: nEgative fiNdings”). The partners, objectives and findings referred to and the various work packages are
p.000015: described on the website www.open-project.eu. The fourth work package will comprise an assessment of the policy
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
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p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
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p.000003:
p.000003: Opinion No 51 of 12 March 2012
p.000003: on the publication of the results of human experimentation
p.000003:
p.000003: Contents
p.000003: Annexes 1 TO 4 of opinion: SEE SEPARATE document 2
p.000003: request for an opinion
p.000003: 3
p.000003: introductory Consideration
p.000004: 4
p.000004: SUMMARY
p.000005: 5
p.000005: 1. Registration and publication
p.000006: 6
p.000006: 1.1. Underreporting of research findings 6
p.000006: 1.2. Prospective registration in a public register 10
p.000006: 1.3. Publication of all research findings 14
p.000006: 2. Role of medical ethics committees
p.000018: 18
p.000018: 2.1. Guide from the Council of Europe intended for Research Ethics Committees (REC) 18
p.000018: 2.2. Directive from the Dutch Central Commission for research involving human subjects (Centrale Commissie voor
p.000018: Mensgebonden Onderzoek, CCMO) 20
p.000018: 3. GENERAL Point OF VIEW AND recommendations 23
p.000018: 3.1. Context
p.000023: 23
p.000023: 3.2. General point of view regarding the publication of research findings 24
p.000023: 3.3. Recommendations
p.000024: 24
p.000024: a. Recommendation regarding the resources of medical ethics committees: a prior condition
p.000024: 24
p.000024: b. Recommendation on the ethical assessment and follow-up of protocols by medical ethics committees
p.000024: 24
p.000024: c. Recommendation in the context of the possible revision of European Directive 2001/20/EC
p.000025: 25
p.000025: ANNEXES 1 TO 4 OF OPINION: SEE SEPARATE DOCUMENT
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
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p.000025:
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p.000025:
p.000025:
p.000025: Final version
p.000002: 2
p.000002:
p.000002: REQUEST FOR AN OPINION
p.000002: On 15 October 2008, Dr. G. Bauherz, President of the Medical Ethics Committee of the Hospitals Iris
p.000002: Sud (HIS, Brussels), submitted the following question to the Advisory Committee on Bioethics (extract
p.000002: from his letter):
p.000002: “When clinical studies are submitted, the HIS Ethics Committee regularly discusses the issue of the
p.000002: publication of findings.
p.000002: In particular as regards studies on therapeutic medicinal products or techniques, we are unaware of what happens
p.000002: to the findings of studies that prove to be negative.
p.000002: We would like to know whether the Advisory Committee has formulated an opinion on this subject and if
p.000002: not, we would like to be able to discuss it with you.”
p.000002:
p.000002: At the plenary meeting of 17 November 2008, the question was declared admissible and allocated to the
p.000002: 'clinical research’ select committee. The author of the question was informed of this in a letter of 19 January
p.000002: 2009. The Committee’s third term of office ended on 20 April 2009 and the question was passed on to the fourth
p.000002: term, which partly explains the length of time taken to compile this opinion.
p.000002:
p.000002: The ‘clinical research’ select committee reformulated the problem as follows:
p.000002: When examining a protocol relating to human experimentation, can/must a medical ethics committee (MEC) check how
p.000002: the findings of the research – whether positive, negative or inconclusive – will be published or made publicly
p.000002: available?
p.000002:
p.000002: There first of all follows an introductory consideration of the concept of ‘clinical trial’ in this opinion. The
p.000002: question, the context and the recommendations are then summarised.
p.000002: The context is set out in points 1 and 2. Point 1 outlines the problem of the underreporting of research findings. The
p.000002: need for the prior or prospective registration of clinical trials and the publication of their findings is thus
p.000002: dealt with. The potential role of medical ethics committees is covered in point 2. Point 3 ends by presenting
p.000002: the general point of view and the recommendations of the Advisory Committee on Bioethics.
p.000002: A few annexes then follow, providing additional information.
p.000002:
p.000002:
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p.000002:
p.000002: Final version
p.000003: 3
p.000003:
p.000003: INTRODUCTORY CONSIDERATION
p.000003: First of all, the concepts that will be used throughout this opinion should be specified. The definition of clinical
p.000003: trials can, in fact, differ depending on the body or organisation concerned.
p.000003:
p.000003: In European Directive 2001/20/EC relating to the implementation of good clinical practices in the conduct of clinical
p.000003: trials on medicinal products for human use, the definition adopted is somewhat narrow: clinical trials are
p.000003: understood to refer only to interventional studies concerning medicinal products (tested on humans). When
p.000003: transposing the European directive in the act of 7 May 2004 on human experimentation, the Belgian
p.000003: legislator took the definition of clinical trial as formulated in the directive (Article 2, 7°):
p.000003:
p.000003: “clinical trial: any investigation in human subjects intended to discover or verify the clinical, pharmacological
p.000003: and/or other pharmaco-dynamic effects of one or more investigational medicinal product(s) and/or to
p.000003: identify any adverse reactions to one or more investigational medicinal products and/or to study
p.000003: absorption, distribution, metabolism and excretion of one or more investigational medicinal
p.000003: products with the object of ascertaining its (their) safety and/or efficacy”.
p.000003:
p.000003: However, the scope of application of the Belgian act covers far more than simply interventional
p.000003: studies with medicinal products, as can be seen from the following definition of the concept of 'experimentation’ in
p.000003: Article 2, 11:
p.000003:
p.000003: “Experimentation: trial, study or investigation in human subjects intended to develop knowledge specific to the
p.000003: exercising of health-care professions as referred to by Royal Decree No 78 of 10 November 1967 on the exercising of
p.000003: health-care professions.”
p.000003:
p.000003: The act provides for an exception to Article 3, §21: purely retrospective studies do not fall within the scope of
p.000003: application of the act.
p.000003:
p.000003: It will be seen later in the opinion that the Dutch legislator has also introduced broader regulation of
p.000003: medical-scientific research than that provided for in the European directive.
p.000003: The Food and Drug Administration (FDA) in the United States also adopts a broader definition of a
p.000003: clinical trial than that formulated in the European directive. The Council of Europe and the World Health
p.000003: Organisation go even further in this definition.
p.000003:
p.000003: In the following text, the term 'clinical trials' should be interpreted in the broad sense, that is in the sense of
p.000003: research carried out on humans, which also corresponds more closely to the scope of application of Belgian law, that is
p.000003: experiments conducted on human subjects that contribute towards the development of knowledge specific to the exercising
p.000003: of health-care professions. When reference is made to European Directive 2001/20/EC, this therefore refers only to
p.000003: interventional studies concerning medicinal products (see also the aforementioned definition of a clinical trial in
p.000003: Belgian law).2
p.000003:
p.000003:
p.000003:
p.000003:
p.000003: 1 Art. 3, §2: “This law does not apply to purely retrospective studies based on past data which are found in patients’
p.000003: dossiers, medical dossiers or administrative dossiers or databases provided that under no circumstances are new data
p.000003: relating to these patients found.”
p.000003: 2 In the introductory report for opinion No 13 of 9 July on human experimentation, the Committee defines the
p.000003: concept of experimentation in point B. It also explains the various phases of biomedical experimentation relating to
p.000003: substances that may be medicinal products, which corresponds to an interventional study concerning
p.000003: medicinal products in this opinion.
p.000003: See web page:
p.000003: www.health.belgium.be/eportal/Healthcare/Consultativebodies/Commitees/Bioethics/Opinions/index.htm?&fodnlan g=fr
p.000003:
p.000003: Final version
p.000004: 4
p.000004:
p.000004: SUMMARY
p.000004: Dr G. Bauherz, Chairman of the Medical Ethics Committee of the IRIS Sud hospitals (HIS, Brussels), put
p.000004: the problem to the Advisory Committee on Bioethics that the members of the medical ethics committee often do not
p.000004: know what happens to the findings of studies concerning therapeutic medicinal products or techniques that prove
p.000004: to be negative.
p.000004:
p.000004: The Advisory Committee on Bioethics reformulated this request for an opinion as follows: When examining a protocol
p.000004: relating to human experimentation, can/must a medical ethics committee (MEC) check the way in which the
p.000004: findings of the research – whether positive, negative or inconclusive – will be published or made publicly
p.000004: available?
p.000004:
p.000004: The opinion takes as a basis the context of the problem of the underreporting of research result (publication bias).
p.000004: Several initiatives have been developed in the past decade that aim to promote the transparency and,
p.000004: consequently, the integrity of scientific research, including initiatives focusing on the mandatory prospective
p.000004: registration of clinical trials in public registers and guidelines on the publication of research findings.
p.000004: The Council of Europe Guide (2010) intended for members of research ethics committees recommends that once
p.000004: their research is finished, researchers should (1) submit a report or a synopsis of their conclusions to the committee
p.000004: that initially assessed the research, and also
p.000004: (2) confirm their initial proposals regarding the publication of the findings in scientific journals or
p.000004: their public communication by other means. In order to thwart the publication of biased research findings, the Council
p.000004: of Europe guide also suggests making ethical approval by ethics committees subject to prospective registration of the
p.000004: protocol in a register that is accessible to the public. These committees should also always ask for all the findings
p.000004: of the research to be made public.
p.000004: As a concrete example, reference can be made to the ‘Research contract assessment’ directive (Richtlijn
p.000004: ‘Beoordeling onderzoekscontract’) in which the Central Dutch Commission for research involving human subjects (Centrale
p.000004: Commissie voor Mensgebonden Onderzoek, CCMO) entrusts to medical-ethical assessment committees (METC) the task
p.000004: of verifying whether the protocols do not contain any unreasonable restrictions with regard to the
p.000004: publication of research findings.
p.000004:
p.000004: Starting from the general point of view that it is a matter of ethical duty to publish, as far as is possible, all
p.000004: findings – whether they are positive, negative or inconclusive – of scientific research carried out on humans, the
p.000004: Advisory Committee on Bioethics makes the following recommendations to the Belgian authorities.
p.000004:
p.000004: a. Medical ethics committees must be given the resources to fulfil their missions correctly.
p.000004: b. Medical ethics committees must be given the mission (1) to assess protocols in the light of the policy on the
p.000004: publication of the research findings and (2) to follow up protocols for which they have issued a positive
p.000004: opinion until the findings are published.
p.000004: c. The issue of the publication of all the findings of research must be tackled at European level,
p.000004: for example in the context of the revision of European Directive 2001/20/EC relating to the implementation of
p.000004: good clinical practice in the conduct of clinical trials on medicinal products for human use.
p.000004:
p.000004:
p.000004:
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p.000004:
p.000004: Final version
p.000005: 5
p.000005:
p.000005: 1. Registration and publication
p.000005: In its opinion No 133, the Advisory Committee on Bioethics considered the ethical problem raised by human
p.000005: experimentation.
p.000005: The issue tackled here is the need for the prospective registration of all clinical trials4 carried out
p.000005: on human subjects and the widest possible publication of their findings in order to prevent the underreporting of
p.000005: scientific discoveries. This relates to the problem of publication bias.
p.000005:
p.000005: 1.1. Underreporting of research findings
p.000005: Research findings may or may not be statistically significant. The classification of findings as positive or negative,
p.000005: favourable or unfavourable, important or of no interest in itself involves interpretation.5 Findings will usually
p.000005: be considered to be positive when they confirm the research assumption set out before the clinical trial: a new
p.000005: medicinal product put to trial, for example, is statistically more significant than the comparator
p.000005: (placebo or standard treatment). 6 Whatever the result, whether it is statistically significant or not, the extent
p.000005: of any differences found should also be examined.
p.000005:
p.000005: When the classification of statistically significant or insignificant findings as 'positive', 'negative' or
p.000005: 'of no interest’ influences their dissemination, underreporting or a publication bias regarding findings may occur.
p.000005: For instance, when positive findings concerning the efficacy of a new medicinal product are disseminated more
p.000005: widely than findings that are less positive or of no interest, this may give rise to an overvaluation of
p.000005: the efficacy of this medicinal product.7
p.000005: NIHR 2010 report
p.000005:
p.000005: In the context of its Health Technology Assessment Programme, in February 2010 the National Institute for Health
p.000005: Research (United Kingdom) published a study report entitled "Dissemination and publication of research
p.000005: findings: an updated review of related biases".
p.000005:
p.000005: As the title indicates, this report is an update of an initial report8 published in July 2000 which concluded in
p.000005: particular that despite the uncertainty surrounding the extent, the orientation and the impact of publication
p.000005: bias, it seems reasonable to conclude that studies
p.000005:
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p.000005:
p.000005: 3 Opinion No 13:
p.000005: www.health.belgium.be/eportal/Healthcare/Consultativebodies/Commitees/Bioethics/Opinions/index.htm?&fodnlan g=fr
p.000005: 4 Broad definition of clinical trial, see also preliminary consideration.
p.000005: 5 Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al. (2010), “Dissemination and publication of research
p.000005: findings: an updated review of related biases”. Health Technol Assess, 14(8), 234 p., p. 2.
p.000005: For the report, hereinafter abbreviated to ‘NIHR report 2010’, see web page: www.hta.ac.uk/project/1627.asp.
p.000005: 6 Rasmussen N, Lee K, Bero L. (2009), “Association of trial registration with the results and conclusions of published
p.000005: trials of new oncology drugs”, Trials, 10:116, see p. 4.
p.000005: See web page: www.trialsjournal.com/content/10/1/116. 7 NIHR report 2010, p. 2.
p.000005: 8 Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ. (2000), “Publication and related biases”, Health Technol Assess,
p.000005: 4(10), 115 p.
p.000005: For the full report, see web page http://www.hta.ac.uk/project/1051.asp.
p.000005:
p.000005: Final version
p.000006: 6
p.000006:
p.000006: which produce conclusive or positive findings are disseminated more and more quickly9 than studies whose
p.000006: findings are inconclusive or negative.10
p.000006: The 2010 update reaches a similar conclusion11, i.e. that the dissemination of research findings is a
p.000006: biased process the real impact of which is unknown. This should be taken into account when taking evidence-based
p.000006: decisions. This updated version makes reference to recent initiatives to promote the prospective registration of
p.000006: clinical trials and guidelines on the reporting of research findings, while stressing that the prospective registration
...
p.000009: 29 See also “WHO clinical trials initiative to protect the public”, Bulletin of the World Health Organization, January
p.000009: 2006, 84(1), pp. 10-11, see p. 11.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p. 237.
p.000009: 30 CCMO Annual report 2010, p. 32.
p.000009: 31 See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”,
p.000009: Australian Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009:
p.000009: Final version
p.000010: 10
p.000010:
p.000010: As explained in the following point, the interest of the prior or prospective registration of clinical trials (phase
p.000010: II, III and IV trials32) is acknowledged on various sides. As regards the disclosure of information on phase I trials
p.000010: or first-into-man studies, however, there is more discussion.33
p.000010: Existing initiatives, points of view and guidelines
p.000010:
p.000010: There follows a non-exhaustive survey of a number of initiatives and points of view/guidelines
p.000010: concerning the prospective registration of research protocols. Some of these are covered in more detail in Annex 1.
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010: 32 The four successive phases of clinical trials are described in the introductory report to Opinion No 13 of 9 July
p.000010: 2001 on human experimentation, issued by the Committee, as follows (see point B. Definitions):
p.000010: “Phase I involves administering the product for the first time, in principle to a small number of volunteers in good
p.000010: health [editor’s note: often healthy volunteers, but not always, for example in the case of anti-cancer products], to
p.000010: assess their tolerance to the product, determine the maximum tolerated by humans and the minimum active dose of the
p.000010: product, and study its pharmacokinetic and pharmaco-dynamic properties.
p.000010: Phase II concerns trails on a limited group of patients suffering from the pathology for which the
p.000010: product is intended, in order to confirm its efficacy, assess its therapeutic interest, assess the relationship
p.000010: between the risks and the advantages linked to its administration and seek the best dose and the best
p.000010: means of administration depending n the effect sought.
p.000010: During phase III, studies are conducted on a large number of patients, usually divided into comparable
p.000010: groups, according to a strict methodology (randomisation). These studies aim to examine tolerance in the medium term
p.000010: and efficacy, so as to e able to estimate the relationship between the benefits and the disadvantages (unwanted effects
p.000010: and cost). This phase is also used to gather information which will be useful for prescribers. If it proves conclusive,
p.000010: the next step is to think about marketing the product and fulfilling the procedures to issue the authorisation to
p.000010: place it on the market.
p.000010: Phase IV comprises the studies conducted once the product has been put on the market. These studies are sued to gain
...
p.000011: (ABR-formulier, General assessment and registration form) are automatically made public as soon as
p.000011: they are entered into ToetsingOnline by the METC which assessed the study. As of 2010, a exception is made
p.000011: for phase-1 studies: the basic data from the ‘ABR’ form are not automatically made public when entered ToetsingOnline
p.000011: by the METC concerned, but six months later37. (See Annex 1, C.).
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011: 34 https://www.clinicaltrialsregister.eu
p.000011: 35 See annex 3, point 1. Introduction; end of second paragraph.
p.000011: 36 See www.who.int/ictrp/en: “The mission of the WHO International Clinical Trials Registry Platform is to ensure that
p.000011: a complete view of research is accessible to all those involved in health care decision making. This will improve
p.000011: research transparency and will ultimately strengthen the validity and value of the scientific evidence base.”
p.000011: 37 CCMO annual report 2010, p. 32 –web page: www.ccmo-
p.000011: online.nl/hipe/uploads/downloads_catc/CCMO%20jaarverslag%202010.PDF
p.000011:
p.000011: Final version
p.000012: 12
p.000012:
p.000012: Belgium (the Advisory Committee on Bioethics and the FAMHP)
p.000012:
p.000012: In Belgium, there are currently two websites on which information relating to clinical trials (experiments) are
p.000012: registered, but these are not accessible to the public.
p.000012:
p.000012: The Advisory Committee on Bioethics manages a website on which medical ethics committees (MEC)
p.000012: report annually on their activities a posteriori. The title and characteristics of experiments submitted to MECs
p.000012: for an opinion are thus reported. This includes both experiments that fall under the Belgian act of 7 May 2004
p.000012: on human experimentation and those that are not covered by its scope of application. The MECs also report on the
p.000012: ethical topics they have covered. On the basis of these data, the Advisory Committee on Bioethics draws up an annual
p.000012: report on the activities of the MECs. This a posteriori report only includes approved data.
p.000012:
p.000012: As regards experiments that fall under the Belgian act but are not interventional clinical studies with
p.000012: medicinal products as referred to in European Directive 2001/20/EC38, a unique Belgian number has to be requested in
p.000012: advance on a website run by the Federal Agency for Medicines and Health Products (FAMHP).
p.000012:
p.000012: Interventional clinical studies on medicinal products referred to by the European directive39 must be prospectively
p.000012: recorded in the EudraCT database, in which a number of information fields are open for public consultation via the
p.000012: Clinical Trials Register.
p.000012:
p.000012: It should be stressed that a project is underway within the FAMHP with a view to developing an interactive website40
p.000012: for the registration and follow-up of clinical trials.
p.000012: The editors (ICMJE)
p.000012:
p.000012: A major initiative has also been taken in the world of publishing. Further to the decision of the International
p.000012: Committee of Medical Journal Editors (ICMJE), in 2004, to henceforth accept for publication only clinical trials
p.000012: that have undergone prospective registration41 in a recognised public register, an increase of over 70 % in the
p.000012: number of clinical trials registered was observed in 2005.42 (See also Annex 1, B.4.).
...
p.000016: are published in scientific reviews, but also inconclusive or negative findings, or all ‘raw’ research findings
p.000016: (raw data). Complete transparency of scientific discoveries also proves necessary to promote medicine that is
p.000016: truly evidence based. Given this interest, however, it is also necessary to take account of the real
p.000016: commercial and economic interests of the pharmaceutical industry, in particular. Nevertheless, more and more
p.000016: initiatives are being taken that aim to achieve complete transparency in research findings.
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016:
p.000016: 58 For more details, see point 1.1. Underreporting of research results – Who is involved? 59 See
p.000016: www.belspo.be/belspo/organisation/publ/Eth_code_fr.stm
p.000016: 60 NIHR report 2010, p. 53.
p.000016: See also web page: www.jnrbm.com: “Journal of Negative Results in BioMedicine is an open access, peer-reviewed, online
p.000016: journal that promotes a discussion of unexpected, controversial, provocative and/or negative results in the context of
p.000016: current tenets.”
p.000016:
p.000016: Final version
p.000017: 17
p.000017:
p.000017: 2. ROLE OF MEDICAL ETHICS COMMITTEES
p.000017: In the context of the ethical examination of a protocol on human experimentation, can/must a medical ethics
p.000017: committee check in what way the research findings – whether positive, negative or inconclusive – will be
p.000017: published or made publicly available? This is the request for an opinion as reformulated by the Committee.
p.000017:
p.000017: The Council of Europe and the Dutch Central Commission for research involving human subjects (Centrale
p.000017: Commissie voor Mensgebonden Onderzoek, CCMO) have recently considered this question.
p.000017:
p.000017:
p.000017: 2.1. Guide from the Council of Europe intended for Research Ethics Committees (REC) 61
p.000017: On 7 February 2011, the Council of Europe published a guide intended for the members of research ethics committees
p.000017: (REC). Article 28 of the additional protocol to the Oviedo Convention on Human Rights and Biomedicine relating
p.000017: to biomedical research already states that when a research project is over, a report or a summary should
p.000017: be drawn up to be forwarded to the medical ethics committee or the competent authorities.
p.000017:
p.000017: The guide refers above all to interventional studies carried out on human subjects. However, it may be supposed that
p.000017: some points, such as access to research findings, are relevant for all biomedical and scientific research projects in
p.000017: which human subjects are involved.62
p.000017: The guide distinguishes three research stages63. Below, some of the recommendations in the guide are briefly
p.000017: compared with the provisions in European Directive 2001/20/EC on interventional studies involving medicinal
p.000017: products and the Belgian act of 7 May 2004 on human experimentation64.
p.000017: a. Before the research starts
...
p.000017: 62 Guide for the members of research ethics committees, 1. The guide: a tool for the members of research ethics
p.000017: committees (REC), paragraph 2.
p.000017: 63 Guide for members of research ethics committees, 5.A.1. Roles and activities of RECs in the research process. 64
p.000017: This act transposes the provision of European directive 2001/20/EC.
p.000017:
p.000017: Final version
p.000018: 18
p.000018:
p.000018: “Another ethical obligation of researchers or the promoters of research is to make the conclusions of the
p.000018: research accessible to the public by publishing them in full using a suitable means. Sometimes, research
p.000018: findings, in particular ‘negative’ research findings are suppressed; such biased publication is not only contrary to
p.000018: the scientific and ethical requirements but also harms patients, for example when unwanted side effects
p.000018: are concealed. Even though several mechanisms have been put in place to improve the transparency
p.000018: of the information reports on research, for example, the obligation to register all clinical trials on
p.000018: medicinal products in a public database before the trials begin (see Chapter 6 – Independent examination of a research
p.000018: project by an REC), the RECs can still help focus on this important issue when research projects that they have
p.000018: examined have finished.”
p.000018:
p.000018: Belgian law stipulates that the medical ethics committee that had issued a opinion positive about an experiment must be
p.000018: informed when it is over. In the case of an interventional study with medicinal products, the competent national body
p.000018: (the Federal Agency for Medicine and Health Products) must also be informed when a project has finished. In this case,
p.000018: the end of the study is also included in the EudraCT database. The Clinical Trials Register also indicates, per
p.000018: protocol, whether the study is ongoing or finished. Neither the Belgian act nor the European directive
p.000018: provides for mandatory publication of the research findings. As has already been mentioned in point 1.3.,
p.000018: the ultimate intention is, however, to include the research findings of clinical trials registered
p.000018: prospectively in this database in the EudraCT database as well, and make them partially public via the Clinical Trials
p.000018: Register.
p.000018:
p.000018: Chapter 6 of the guide focuses on the content of an independent examination of a research project by an
p.000018: REC. Point 6.C concerns the information to be provided to the REC, which this body has to examine. This information
p.000018: includes the research findings (6.C.20) for which the following recommendations are made:
p.000018:
p.000018: - making research findings available to the REC and participants:
p.000018: “[…] when the research is over, the researchers must send the REC a report or a synopsis of the findings obtained.
p.000018: It is also at this stage that the researchers should confirm their initial proposals concerning the publication
p.000018: of the findings in scientific journals or making them publicly available by other means.
p.000018: The general research conclusions should be made accessible to all participants who so wish, in an
p.000018: understandable form. If the communication of this information also has to respect the interests of
p.000018: third parties, such as the promoter of the research or the researchers themselves, this should not
p.000018: constitute an argument to deprive participants of their legitimate right to know the result of the research in which
p.000018: they took part. However, a reasonable period of time may be acceptable.”
p.000018:
p.000018: Neither the European directive nor the Belgian act expressly mention that at the end of the experiment (which must
p.000018: be reported), the findings also have to be made available to the medical ethics committee that issued a
p.000018: favourable opinion for the research project or the competent authority in the case of an interventional study
p.000018: with medicinal products (FAMHP) or the participants in the trial.
p.000018:
p.000018: As we have already mentioned, a draft text from the European Commission proposes that in future, the findings of
p.000018: clinical trials should be made publicly available via the Clinical Trials Register at the latest twelve months after
p.000018: the end of the trial – whether it was completed or interrupted prematurely. For paediatric trials, this, this
p.000018: period of time is reduced to six months. (See Annex 1, A.2.).
p.000018:
p.000018: - publication of research findings for scientific and health-care purposes: (extract from the Council of Europe
p.000018: guide)
p.000018:
p.000018:
p.000018:
p.000018:
p.000018: Final version
p.000019: 19
p.000019:
p.000019: “lt is important to make research findings publicly available, irrespective of whether the research
p.000019: assumption has been confirmed (positive result) or invalidated (negative result) or these findings do not
p.000019: lead to a conclusion.” […] The additional protocol to the Oviedo Convention on biomedical research makes it mandatory
p.000019: for researchers to submit a report or a summary to the REC at the end of the study. Should study end prematurely, a
p.000019: report including the reasons for this should also be submitted to the REC. Moreover, the protocol requires the
p.000019: publication of findings within a reasonable period of time, as well as the communication of the
p.000019: conclusions of the research to participants who so request. The REC must therefore have access to elements
p.000019: enabling it to ensure that the researchers have defined a publication policy, that they have discussed the matter
p.000019: with all external promoters so that they are not prevented from publishing the findings owing to contractual
p.000019: obligations. A reasonable period of time for publication is acceptable, in not order to adversely affect a
p.000019: patent application. However, this argument should not constitute a pretext for the unlimited retention of the
p.000019: findings.
p.000019: Particular concerns have been expressed regarding the publication of research findings on potential new
p.000019: treatments, biased notably owing to the concealment of ‘unfavourable’ findings. To overcome this practice and
p.000019: ensure that the findings are published, researchers should register all research projects before they begin in a
p.000019: register that is accessible to the public. The members of the REC can encourage this effort at transparency by making
p.000019: this registration a condition for their positive opinion regarding the ethical acceptability of the research
p.000019: project. Although national legislation does not allow the opinion to be conditioned by a request
p.000019: like this, the REC should at least use its position to request that all the findings be made publicly
p.000019: available.”
p.000019:
p.000019: Neither European Directive 2001/20/EC nor the Belgian law of 7 May 2004 expressly mentions that a
p.000019: medical ethics committee is competent to monitor the publication policy adopted for a research project. In the
p.000019: Netherlands, this provision is, however, made.
p.000019:
p.000019:
p.000019: 2.2. Directive from the Dutch Central Commission for research involving human subjects (Centrale
p.000019: Commissie voor Mensgebonden Onderzoek, CCMO)
p.000019: On 13 November 2008, the Dutch Central Commission for research involving human subjects (Centrale
p.000019: Commissie voor Mensgebonden Onderzoek, CCMO) published the ‘Research contract assessment’ directive
p.000019: (Richtlijn ‘Beoordeling onderzoekscontract’) intended for medical-ethical assessment committees (Medisch-ethische
p.000019: toetsingscommissies, METC), which entered into force in 2009. In 2010, this directive was assessed, resulting on 30
p.000019: August 2011 in the revised ‘Research contract assessment’ directive65. Article 3 became Article 4, in which point c)
p.000019: was reworded and point d) added.
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019:
p.000019: 65 Revised CCMO ‘Research contract assessment’ directive of 30 August 2011:
p.000019: www.ccmo- online.nl/hipe/uploads/downloads_catc/CCMO%20jaarverslag%202010.PDF
p.000019: (initial CCMO ‘Research contract assessment’ directive of 13 November 2008:
...
p.000020: to the definition of ‘promoter’ in the Belgian act of 7 May 2004 on human experimentation;
p.000020: (uitvoerder) “g. the party carrying out the scientific research: doctor or person referred to in Article 3, e, in
p.000020: charge of carrying out the scientific research at a given site. If the actual carrying out of the
p.000020: research is entrusted to an employee or other auxiliary, the party uses this person is deemed to be the one
p.000020: carrying out the scientific research’, which corresponds to the definition of ‘investigator’ in the Belgian act of 7
p.000020: May 2004 on human experimentation.
p.000020: Original version:
p.000020: “f. degene die het wetenschappelijk onderzoek verricht: een persoon, bedrijf, instelling of organisatie
p.000020: die de verantwoordelijkheid op zich neemt voor het starten, het beheer of de financiering van het
p.000020: wetenschappelijk onderzoek;
p.000020: g. degene die het wetenschappelijk onderzoek uitvoert: een arts of een in artikel 3, onder e, bedoelde persoon, die
p.000020: verantwoordelijk is voor de uitvoering van het wetenschappelijk onderzoek op een bepaalde locatie. Indien
p.000020: de feitelijke uitvoering geschiedt door een werknemer of een andere hulppersoon, wordt degene die van deze persoon
p.000020: gebruik maakt aangemerkt als degene die het onderzoek uitvoert.”
p.000020:
p.000020: Final version
p.000021: 21
p.000021:
p.000021: reasonable period of time or has, for instance, had the opportunity to submit patent applications. It is
p.000021: important for the parties to succeed in resolving any differences of opinion together and for none of the
p.000021: parties concerned to have a veto.”
p.000021:
p.000021: The Dutch CCMO thus expressly gives the medical-ethical assessment committees (METC) the task of checking
p.000021: whether research agreements contain unreasonable limitations on the publication of research findings.
p.000021: Moreover, the same directive aims to limit the premature interruption of scientific research projects (Article 3) to
p.000021: the extent that, in the context of these projects, trial subjects have already been subjected to experimental
p.000021: interventions.
p.000021: Or, to take the terms used by the CCMO in its 2010 annual report (p. 42): (free translation) “The directive aims to
p.000021: monitor the interest of the publication of research findings and prevent the premature ending of research for
p.000021: non-medical-scientific reasons.
p.000021: In fact, in this case, the trial subjects included until then could have taken part in clinical research for
p.000021: nothing.”67
p.000021: It may be concluded that the Netherlands are pioneers and are ahead of European initiatives and developments. Whereas
p.000021: the public was able to consult the basic data of research protocols relating to medical-scientific
p.000021: research (‘WMO’ act- medisch-wetenschappelijk onderzoek) from 2009 (https://ToetsingOnline.ccmo.nl), this
p.000021: possibility has only existed for research protocols included in the EudraCT database since 22 March 2011. It should
p.000021: also be pointed out in this context that the scope of application of the Dutch act is wider than that of European
p.000021: Directive 2001/20/EC, in which respect it is in line with the Belgian act. To date, no results have been included in
p.000021: the ToetsingOnline public register, but in the future, the CCMO does intend to record a summary. (See Annex 1, C.).
p.000021:
...
p.000022: makes the following recommendations: once their research is complete, researchers must (1) forward a report or a
p.000022: synopsis of their conclusions to the medical ethics committee which initially assessed the research, and (2)
p.000022: confirm their initial proposals concerning the publication of findings in scientific journals or their
p.000022: public communication by other means. In order to thwart the publication of biased research findings, it is
p.000022: recommended that ethical approval by the ethical committees be made subject to prospective registration of the protocol
p.000022: in a public register. These committees should also always request that the research findings be made public.
p.000022: In the Netherlands, the ‘Research contract assessment’ directive (Richtlijn ‘Beoordeling onderzoekscontract’)
p.000022: has been in force since 2009. According to this directive, the Dutch Central Commission for research
p.000022: involving human subjects (Centrale Commissie voor Mensgebonden Onderzoek, CCMO) gives medical-ethical assessment
p.000022: committees (METC) the tasks of checking whether protocols contain unreasonable restrictions as regards the
p.000022: publication of research findings.
p.000022:
p.000022: In this context, the Advisory Committee on Bioethics first sets out its general point of view regarding the
p.000022: publication of research findings. This is followed by a number of recommendations in response to
p.000022: the actual request for an opinion which has been reformulated as follows:
p.000022: When examining a protocol on human experimentation, can/must a medical ethics committee (MEC)
p.000022: check how the research findings – whether positive, negative or inconclusive – will be published or
p.000022: made publicly available?
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022:
p.000022: Final version
p.000023: 23
p.000023:
p.000023: 3.2. General point of view regarding the publication of research findings
p.000023: The Advisory Committee on Bioethics believes that as far as possible, the publication of all the findings of scientific
p.000023: research carried out on human subjects – whether they are positive, negative or inconclusive – is a matter of ethical
p.000023: duty.
p.000023:
p.000023: By taking part voluntarily in an experiment, the subjects who agree to undergo this – both healthy volunteers and
p.000023: patients – in fact contribute to the development of scientific knowledge, which is to benefit the entire
p.000023: community. Whatever the origin (community and/or other promoters) of the resources used for scientific
p.000023: research on humans, the findings of human experimentation must be made publicly available, if only
p.000023: because the experimentation is carried out on humans. Moreover, when the community provides the research
p.000023: resources, it goes without saying that it is also entitled to the publication of the research findings. The choices
p.000023: and decisions made in terms of the health economy are also based on scientific findings. Distorting these
p.000023: findings can lead to less suitable strategic decisions and therefore have consequences, in particular in
p.000023: economic terms (inadequate funding, wastage, etc.), for society as a whole.
p.000023:
p.000023: It should be pointed out here that the term ‘to make publicly available’ (‘openbaar maken’, ‘rendre public’) has a
p.000023: broader meaning that 'to publish’ ('publiceren'/'publier').
p.000023:
p.000023: 3.3. Recommendations
p.000023: a. Recommendation regarding the resources of medical ethics committees: a prior condition
p.000023: In this context, the Committee refers to the comment it made in the introductory report relating to
p.000023: opinion No 13 of 9 July 2001 on human experimentation, point E, 4, c, end of paragraph 2: “real means (secretariat,
p.000023: staff) must be allocated to existing ethics committees and a training programme must be gradually developed.”
p.000023:
p.000023: The Committee recalls its plea here. The possible development of the missions of medical ethics committees must
p.000023: be accompanied by greater professional support for these committees so that they can carry out their
p.000023: tasks properly. This is also a prior condition for the following recommendation.
p.000023:
p.000023: b. Recommendation on the ethical assessment and follow-up of protocols by medical ethics committees
p.000023: The Advisory Committee on Bioethics recommends to the Belgian authorities, following the example of the Dutch Central
p.000023: Commission for research involving human subjects (Centrale Commissie voor Mensgebonden Onderzoek, CCMO), that medical
p.000023: ethics committees should be entrusted with the task of checking protocols with regard to the policy adopted for the
p.000023: publication of research findings. This means:
p.000023: - that a protocol should contain clear information about the terms under which the research findings will
p.000023: be published or made publicly available;
p.000023: - that the promoter should not be in a position to impose unreasonable restrictions as regards
p.000023: publication: promoters cannot ban or prevent the publication of negative findings; they cannot make their
p.000023: authorisation for publication mandatory, etc.
p.000023:
p.000023: In order to safeguard the interests of the promoter, the Committee feels it is acceptable to for latter to be able to
p.000023: request the observance of a reasonable period – of about one year – between the moment when the findings of the
p.000023: research become available and the time they are published.
p.000023:
p.000023:
p.000023:
p.000023: Final version
p.000024: 24
p.000024:
p.000024: The Advisory Committee on Bioethics recommends expressly entrusting the medical ethics committees with the task of
p.000024: following the protocols for which they have issued a positive opinion until the findings are published.
p.000024:
p.000024: c. Recommendation in the context of the possible revision of European Directive 2001/20/EC
p.000024: The problem of the publication of all research findings is complex and requires an approach that goes beyond the limits
p.000024: of Belgian territory. The Committee therefore recommends to the Belgian authorities that this problem should be
p.000024: considered at European level. In the context of the current assessment/revision of European Directive 2001/20/CE
p.000024: relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal
p.000024: products for human use, the Advisory Committee on Bioethics believes that it is advisable to hold a debate on this
p.000024: issue.
p.000024:
p.000024: ***
p.000024:
p.000024: Annexes 1 to 4 of the opinion are included in a separate document
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024:
p.000024: Final version
p.000025: 25
p.000025:
p.000025: The opinion was prepared in the select commission 2010/1, consisting of:
p.000025:
p.000025: Joint chairpersons
p.000025: Marc Bogaert Andre Herchuelz
p.000025: Reporter
p.000025: Marc Bogaert
p.000025:
p.000025:
p.000025: Members
p.000025:
p.000025: Mylène Baum Paul Cosyns Patrick Cras Yvonne Denier Martin Hiele Guy Lebeer
p.000025: Jean-Marie Maloteaux Marie-Geneviève Pinsart Robert Rubens
p.000025:
p.000025:
p.000025: Member of the Bureau
p.000025: Paul Schotsmans
p.000025:
p.000025: Member of the secretariat
p.000025:
p.000025: Veerle Weltens
p.000025:
p.000025:
p.000025: The working documents of the select commission 2010/1 – request for opinion, personal contributions of the members,
p.000025: minutes of the meetings, documents consulted – are stores as Annexes 2010/1 at the Committee’s documentation
p.000025: centre, where they may be consulted and copied.
p.000025:
p.000025: ***
p.000025:
p.000025: This opinion is available at www.health.belgium.be/bioeth, under the heading “opinions”.
p.000025:
p.000025:
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p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025:
p.000025: Final version
...
Economic / Economic/Poverty
Searching for indicator poor:
(return to top)
p.000009: The 2010 annual report from the Dutch Central Commission for research involving human subjects (Centrale Commissie
p.000009: voor Mensgebonden Onderzoek, CCMO) also stresses that patients are increasingly showing an interest in
p.000009: research relating to ‘their’ illness and sometimes seek specifically to take part in clinical trials
p.000009: through which they can access innovative treatments.30
p.000009: This transparency also enables promoters to deploy their resources in areas of study where there is still little
p.000009: evidence-based knowledge. Those who produce summaries of research findings, including the authors of systematic
p.000009: reviews, meta-analyses and practice guidelines, can thus efficiently and univocally identify all the trials that have
p.000009: been conducted or are still ongoing in their field of interest.31
p.000009:
p.000009:
p.000009: 26 Idem, see p. 414.
p.000009: See also NIHR report 2010, p. 53.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009: 27 Original version: “Every clinical trial must be registered in a publicly accessible database before recruitment of
p.000009: the first subject.”
p.000009: 28 Ghersi D, Clarke M, Berlin J, Gülmezoglu AM, Kush R, Lumbiganon P, Moher D, Rockhold F, Sim I, Wager
p.000009: E. (2008), “Reporting the findings of clinical trials: a discussion paper”, Bulletin of the World Health
p.000009: Organization, 86(6), pp. 492-493, see p. 492.
p.000009: See also Chalmers I, Altman DG. (1999), “How can medical journals help prevent poor medical research?
p.000009: Some opportunities presented by electronic publishing”, Lancet, vol. 353, pp. 490-493, see p. 491.
p.000009: 29 See also “WHO clinical trials initiative to protect the public”, Bulletin of the World Health Organization, January
p.000009: 2006, 84(1), pp. 10-11, see p. 11.
p.000009: See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”, Australian
p.000009: Journal of Physiotherapy, vol. 52, pp. 237-239, see p. 237.
p.000009: 30 CCMO Annual report 2010, p. 32.
p.000009: 31 See also Askie L, Ghersi D, Simes J. (2006), “Prospective registration of clinical trials”,
p.000009: Australian Journal of Physiotherapy, vol. 52, pp. 237-239, see p 237.
p.000009:
p.000009: Final version
p.000010: 10
p.000010:
p.000010: As explained in the following point, the interest of the prior or prospective registration of clinical trials (phase
p.000010: II, III and IV trials32) is acknowledged on various sides. As regards the disclosure of information on phase I trials
p.000010: or first-into-man studies, however, there is more discussion.33
p.000010: Existing initiatives, points of view and guidelines
p.000010:
p.000010: There follows a non-exhaustive survey of a number of initiatives and points of view/guidelines
p.000010: concerning the prospective registration of research protocols. Some of these are covered in more detail in Annex 1.
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
p.000010:
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000018: Register.
p.000018:
p.000018: Chapter 6 of the guide focuses on the content of an independent examination of a research project by an
p.000018: REC. Point 6.C concerns the information to be provided to the REC, which this body has to examine. This information
p.000018: includes the research findings (6.C.20) for which the following recommendations are made:
p.000018:
p.000018: - making research findings available to the REC and participants:
p.000018: “[…] when the research is over, the researchers must send the REC a report or a synopsis of the findings obtained.
p.000018: It is also at this stage that the researchers should confirm their initial proposals concerning the publication
p.000018: of the findings in scientific journals or making them publicly available by other means.
p.000018: The general research conclusions should be made accessible to all participants who so wish, in an
p.000018: understandable form. If the communication of this information also has to respect the interests of
p.000018: third parties, such as the promoter of the research or the researchers themselves, this should not
p.000018: constitute an argument to deprive participants of their legitimate right to know the result of the research in which
p.000018: they took part. However, a reasonable period of time may be acceptable.”
p.000018:
p.000018: Neither the European directive nor the Belgian act expressly mention that at the end of the experiment (which must
p.000018: be reported), the findings also have to be made available to the medical ethics committee that issued a
p.000018: favourable opinion for the research project or the competent authority in the case of an interventional study
p.000018: with medicinal products (FAMHP) or the participants in the trial.
p.000018:
p.000018: As we have already mentioned, a draft text from the European Commission proposes that in future, the findings of
p.000018: clinical trials should be made publicly available via the Clinical Trials Register at the latest twelve months after
p.000018: the end of the trial – whether it was completed or interrupted prematurely. For paediatric trials, this, this
p.000018: period of time is reduced to six months. (See Annex 1, A.2.).
p.000018:
p.000018: - publication of research findings for scientific and health-care purposes: (extract from the Council of Europe
p.000018: guide)
p.000018:
p.000018:
p.000018:
p.000018:
p.000018: Final version
p.000019: 19
p.000019:
p.000019: “lt is important to make research findings publicly available, irrespective of whether the research
p.000019: assumption has been confirmed (positive result) or invalidated (negative result) or these findings do not
p.000019: lead to a conclusion.” […] The additional protocol to the Oviedo Convention on biomedical research makes it mandatory
p.000019: for researchers to submit a report or a summary to the REC at the end of the study. Should study end prematurely, a
p.000019: report including the reasons for this should also be submitted to the REC. Moreover, the protocol requires the
p.000019: publication of findings within a reasonable period of time, as well as the communication of the
p.000019: conclusions of the research to participants who so request. The REC must therefore have access to elements
p.000019: enabling it to ensure that the researchers have defined a publication policy, that they have discussed the matter
...
General/Other / declaration of helsinki
Searching for indicator helsinki:
(return to top)
p.000008: do not do justice to those who take part in trials voluntarily in a spirit of altruism.
p.000008: Another consequence of this may be that limited resources and funds are not used to best effect and are therefore
p.000008: wasted.
p.000008: Moreover, this jeopardises the integrity of scientific research. When striking research findings are more
p.000008: widely disseminated than inconclusive findings, this represents a threat to the validity of a research synopsis.22
p.000008: Which players are involved?
p.000008:
p.000008: The NIHR 2010 report stipulated that underreporting of research findings or a publication bias may result from a
p.000008: convergence of the interests of the researchers, peer reviewers, editors and sponsors, while at the same time
p.000008: pointing out that they may be responsible to differing degrees. Despite the fact that various complex
p.000008: factors play a role in the phenomenon of publication bias, the NIHR report states that it is possible
p.000008: to prevent publication bias to a certain extent and reduce its impact. The report puts forward measures to this end,
p.000008: including an adaptation of the policy on the publication of research findings, the possibility of electronic
p.000008: publication, an open access policy, the prospective registration of studies and the setting up of large-scale
p.000008: studies to confirm small-scale research findings.23
p.000008: The World Medical Association also sets out in Article 30 of the sixth version of the Declaration of
p.000008: Helsinki (Seoul, October 2008) a series of ethical obligations for the players concerned:
p.000008: "Authors, editors and publishers all have ethical obligations with regard to the publication of the results of
p.000008: research. Authors have a duty to make publicly available the results of their research on human subjects and are
p.000008: accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical
p.000008: reporting. Negative and inconclusive as well as positive results should be published or otherwise made
p.000008: publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in
p.000008: the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted
p.000008: for publication."24
p.000008: Iain Chalmers25 also stresses the responsibility of research ethics committees. These committees do but half
p.000008: their job when they approve a clinical trial, but do not then check whether the study is undertaken in line with the
p.000008: dossier submitted and whether the research findings have been adequately reported.
p.000008:
p.000008: On the basis of the NIHR report 2010, it may be concluded that the underreporting of research findings
p.000008: is a complex problem, which is important given the impact it exerts on the integrity of scientific research. Many
p.000008: articles as well as the NIHR report single out the need to
p.000008:
p.000008: See also Sandercock P. (2011 copyright) “Negative results: why do they need to be published?”, International Journal of
p.000008: Stroke, Vol 7, January 2012, pp. 32-33, see p. 32.
...
p.000008: published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of
p.000008: interest should be declared in the publication. Reports of research not in accordance with the principles of this
p.000008: Declaration should not be accepted for publication.”
p.000008: 25 Chalmers I. “Underreporting research is scientific misconduct”, abridged version in Ethical and
p.000008: regulatory aspects of clinical research: readings and commentary, Ezekiel JE et al., Johns Hopkins University Press,
p.000008: 2003, pp. 411-414 , see pp. 413-414.
p.000008:
p.000008: Final version
p.000009: 9
p.000009:
p.000009: (1) register the protocol data in public registers (including the definition of primary outcomes) in
p.000009: advance and (2) make all research findings accessible.
p.000009:
p.000009: 1.2. Prospective registration in a public register
p.000009: The registration of clinical trials in a public register before they begin is a first step that make it
p.000009: possible to detect underreporting or a publication bias and check whether there is risk of the biased
p.000009: presentation of scientific discoveries. Once this registration has been done, it is in fact possible to check
p.000009: later on whether the findings of a clinical trial have been published or publicly disclosed. It is also possible to
p.000009: detect whether the trial is still ongoing or has been prematurely interrupted and why. The reported research findings
p.000009: can also be compared with the research assumption or assumptions initially registered.26
p.000009: It should be noted that in the sixth version of the Declaration of Helsinki (Seoul, October 2008), a new Article
p.000009: 19 was inserted which expressly mentions the need for the prospective registration of clinical trials: (free
p.000009: translation)
p.000009: "Every clinical trial must be registered in a publicly accessible database before recruitment of the first
p.000009: subject."27
p.000009: In a working document28 from the World Health Organisation (WHO), the following advantages are
p.000009: associated with the prospective registration of clinical trials in public registers:
p.000009: - this registration is likely to be facilitate the recruitment of participants in clinical trials as it is
p.000009: also a means of informing potential participants and care providers of the existence of studies;29
p.000009: - the pointless duplication of a study already underway elsewhere can be avoided.
p.000009:
p.000009: The 2010 annual report from the Dutch Central Commission for research involving human subjects (Centrale Commissie
p.000009: voor Mensgebonden Onderzoek, CCMO) also stresses that patients are increasingly showing an interest in
p.000009: research relating to ‘their’ illness and sometimes seek specifically to take part in clinical trials
p.000009: through which they can access innovative treatments.30
p.000009: This transparency also enables promoters to deploy their resources in areas of study where there is still little
p.000009: evidence-based knowledge. Those who produce summaries of research findings, including the authors of systematic
p.000009: reviews, meta-analyses and practice guidelines, can thus efficiently and univocally identify all the trials that have
p.000009: been conducted or are still ongoing in their field of interest.31
p.000009:
...
p.000015: the possibilities of overcoming the underreporting of negative findings (to Overcome the failure to Publish
p.000015: nEgative fiNdings”). The partners, objectives and findings referred to and the various work packages are
p.000015: described on the website www.open-project.eu. The fourth work package will comprise an assessment of the policy
p.000015: and procedures of medical ethics committees as regards the prevention of publication bias.56
p.000015:
p.000015: The Council of Europe (European Convention on Human Rights and Biomedicine)
p.000015:
p.000015: In the additional protocol to the Oviedo Convention on Human Rights and Biomedicine, relating to
p.000015: biomedical research, the Council of Europe also devoted an article to the availability of research findings.
p.000015: The principles of this were developed further in the guide published recently and intended for the members of
p.000015: ethics committees who assess protocols. In this guide, the Council of Europe also covers the role of these
p.000015: committees, in that they have to ensure that research findings are made public. We will return to this in
p.000015: more detail in point 2 concerning the ‘Role of medical ethics committees’.
p.000015:
p.000015: The World Health Organisation (WHO)
p.000015:
p.000015: Within the World Health Organisation, a working group has reached the following conclusion (see below, Annex 1, B.2.):
p.000015: "The findings of all clinical trials must be made publicly available".57 The World Medical Association (WMA)
p.000015: Declaration of Helsinki
p.000015:
p.000015: Governments should consider requiring all research involving more than minimal risk to be registered and results
p.000015: reported”.
p.000015: 54 Document of 1 June 2010 bearing reference SANCO/C/8/SF D(2010) 326416: Implementing technical guidance – List of
p.000015: fields for result-related information to be submitted to the 'EudraCT' clinical trials database, and to be made public,
p.000015: in accordance with Article 57 (2) of Regulation (EC) No 726/2004 and Article 41 of Regulation (EC) No
p.000015: 1901/2006 and their implementing guidelines 2008/C168/02 and 2009/C28/01, Draft – submitted for public
p.000015: consultation. See page web: http://ec.europa.eu/health/files/clinicaltrials/technical_guidance_en.pdf
p.000015: 55 This register will be developed gradually.
p.000015: 56 “Work Package 4: Evaluation of policies and procedures of research ethics committees to prevent and monitor
p.000015: publication bias.”
p.000015: 57 Original version: “The findings of all clinical trials must be made publicly available”.
p.000015:
p.000015: Final version
p.000016: 16
p.000016:
p.000016: As already mentioned, in the sixth version of the Declaration of Helsinki (Seoul, October 2008), Article
p.000016: 30 stresses the interest of complete transparency in the publication of the findings of clinical research
p.000016: and states that the authors, editors and publishers all have ethical obligations as regards the publication
p.000016: of research findings.58
p.000016: Scientific organisations
p.000016:
p.000016: The ‘Code of ethics of scientific research in Belgium’59 is a joint initiative of the Academie Royale des Sciences,
p.000016: des Lettres et des Beaux Arts de Belgique, the Academie Royale de Médecine de Belgique, the Koninklijke
p.000016: Vlaamse Academie van België voor Wetenschappen en Kunsten and the Koninklijke Academie voor Geneeskunde van België,
p.000016: supported by the SPP Politique scientifique. This code sets out the main principles of ethically justified scientific
p.000016: practice.
p.000016:
p.000016: European scientific organisations also stress the need to make publicly available all the findings of
p.000016: clinical trials and to this end, to develop integrated databases for clinical research. (See Annex 1, B.5 et
p.000016: B.6).
p.000016:
p.000016: The CONSORT group is an international network which includes researchers (trialists), methodologists and
p.000016: editors of specialised medical reviews. This group has drawn up a declaration – the most recent CONSORT
p.000016: statement dated from 2010 – setting out a minimum set of evidence-based recommendations for the reporting of randomised
p.000016: clinical trials (RCTs) (www.consort-statement.org).
p.000016:
p.000016: The EQUATOR project also grew out of this group in 2006. It aims to improve the reliability and value of medical
...
General/Other / oviedo
Searching for indicator oviedo:
(return to top)
p.000015: all clinical trials registered is not yet possible at the moment, but according to a draft text from the European
p.000015: Commission dated 1 June 201054 which has been submitted for public consultation, this is the aim55. For clinical
p.000015: trials, the proposal is for the findings to be sent to the EMA at the latest twelve months after the
p.000015: end of the trial – whether this ended as planned or was interrupted prematurely – so that the EMA can
p.000015: include the findings in the EudraCT database. For paediatric trials, this period is reduced to six months. The
p.000015: findings should also be accessible to the public via the Clinical Trials Register within five working days after a
p.000015: validated data set has been sent to the EMA (see below, Annex 1, A.2.).
p.000015:
p.000015: The OPEN project jointly funded by the European Commission (7th framework programme) was started up at the end of
p.000015: 2011. This two-year project ran from 1 November 2011 to 31 October 2013. Its main aim was to examine
p.000015: the possibilities of overcoming the underreporting of negative findings (to Overcome the failure to Publish
p.000015: nEgative fiNdings”). The partners, objectives and findings referred to and the various work packages are
p.000015: described on the website www.open-project.eu. The fourth work package will comprise an assessment of the policy
p.000015: and procedures of medical ethics committees as regards the prevention of publication bias.56
p.000015:
p.000015: The Council of Europe (European Convention on Human Rights and Biomedicine)
p.000015:
p.000015: In the additional protocol to the Oviedo Convention on Human Rights and Biomedicine, relating to
p.000015: biomedical research, the Council of Europe also devoted an article to the availability of research findings.
p.000015: The principles of this were developed further in the guide published recently and intended for the members of
p.000015: ethics committees who assess protocols. In this guide, the Council of Europe also covers the role of these
p.000015: committees, in that they have to ensure that research findings are made public. We will return to this in
p.000015: more detail in point 2 concerning the ‘Role of medical ethics committees’.
p.000015:
p.000015: The World Health Organisation (WHO)
p.000015:
p.000015: Within the World Health Organisation, a working group has reached the following conclusion (see below, Annex 1, B.2.):
p.000015: "The findings of all clinical trials must be made publicly available".57 The World Medical Association (WMA)
p.000015: Declaration of Helsinki
p.000015:
p.000015: Governments should consider requiring all research involving more than minimal risk to be registered and results
p.000015: reported”.
p.000015: 54 Document of 1 June 2010 bearing reference SANCO/C/8/SF D(2010) 326416: Implementing technical guidance – List of
p.000015: fields for result-related information to be submitted to the 'EudraCT' clinical trials database, and to be made public,
p.000015: in accordance with Article 57 (2) of Regulation (EC) No 726/2004 and Article 41 of Regulation (EC) No
p.000015: 1901/2006 and their implementing guidelines 2008/C168/02 and 2009/C28/01, Draft – submitted for public
...
p.000016:
p.000016: 58 For more details, see point 1.1. Underreporting of research results – Who is involved? 59 See
p.000016: www.belspo.be/belspo/organisation/publ/Eth_code_fr.stm
p.000016: 60 NIHR report 2010, p. 53.
p.000016: See also web page: www.jnrbm.com: “Journal of Negative Results in BioMedicine is an open access, peer-reviewed, online
p.000016: journal that promotes a discussion of unexpected, controversial, provocative and/or negative results in the context of
p.000016: current tenets.”
p.000016:
p.000016: Final version
p.000017: 17
p.000017:
p.000017: 2. ROLE OF MEDICAL ETHICS COMMITTEES
p.000017: In the context of the ethical examination of a protocol on human experimentation, can/must a medical ethics
p.000017: committee check in what way the research findings – whether positive, negative or inconclusive – will be
p.000017: published or made publicly available? This is the request for an opinion as reformulated by the Committee.
p.000017:
p.000017: The Council of Europe and the Dutch Central Commission for research involving human subjects (Centrale
p.000017: Commissie voor Mensgebonden Onderzoek, CCMO) have recently considered this question.
p.000017:
p.000017:
p.000017: 2.1. Guide from the Council of Europe intended for Research Ethics Committees (REC) 61
p.000017: On 7 February 2011, the Council of Europe published a guide intended for the members of research ethics committees
p.000017: (REC). Article 28 of the additional protocol to the Oviedo Convention on Human Rights and Biomedicine relating
p.000017: to biomedical research already states that when a research project is over, a report or a summary should
p.000017: be drawn up to be forwarded to the medical ethics committee or the competent authorities.
p.000017:
p.000017: The guide refers above all to interventional studies carried out on human subjects. However, it may be supposed that
p.000017: some points, such as access to research findings, are relevant for all biomedical and scientific research projects in
p.000017: which human subjects are involved.62
p.000017: The guide distinguishes three research stages63. Below, some of the recommendations in the guide are briefly
p.000017: compared with the provisions in European Directive 2001/20/EC on interventional studies involving medicinal
p.000017: products and the Belgian act of 7 May 2004 on human experimentation64.
p.000017: a. Before the research starts
p.000017: The guide states that the RECs should assess the ethical acceptability of biomedical research projects (‘their main
p.000017: objective’).
p.000017:
p.000017: b. During the research
p.000017: According to the guide, the RECs should follow up the research projects they have approved and may need to re-examine
p.000017: them owing to new and relevant knowledge acquired during the research.
p.000017:
p.000017: c. After the research
p.000017: The guide states that the role of the REC in this stage is still fairly limited:
p.000017: “The role of the REC, once the research is over, is currently limited […]. It is generally considered
p.000017: that this is not the period when recourse to the expertise of the REC is the most important. Moreover, the RECs
...
p.000018: constitute an argument to deprive participants of their legitimate right to know the result of the research in which
p.000018: they took part. However, a reasonable period of time may be acceptable.”
p.000018:
p.000018: Neither the European directive nor the Belgian act expressly mention that at the end of the experiment (which must
p.000018: be reported), the findings also have to be made available to the medical ethics committee that issued a
p.000018: favourable opinion for the research project or the competent authority in the case of an interventional study
p.000018: with medicinal products (FAMHP) or the participants in the trial.
p.000018:
p.000018: As we have already mentioned, a draft text from the European Commission proposes that in future, the findings of
p.000018: clinical trials should be made publicly available via the Clinical Trials Register at the latest twelve months after
p.000018: the end of the trial – whether it was completed or interrupted prematurely. For paediatric trials, this, this
p.000018: period of time is reduced to six months. (See Annex 1, A.2.).
p.000018:
p.000018: - publication of research findings for scientific and health-care purposes: (extract from the Council of Europe
p.000018: guide)
p.000018:
p.000018:
p.000018:
p.000018:
p.000018: Final version
p.000019: 19
p.000019:
p.000019: “lt is important to make research findings publicly available, irrespective of whether the research
p.000019: assumption has been confirmed (positive result) or invalidated (negative result) or these findings do not
p.000019: lead to a conclusion.” […] The additional protocol to the Oviedo Convention on biomedical research makes it mandatory
p.000019: for researchers to submit a report or a summary to the REC at the end of the study. Should study end prematurely, a
p.000019: report including the reasons for this should also be submitted to the REC. Moreover, the protocol requires the
p.000019: publication of findings within a reasonable period of time, as well as the communication of the
p.000019: conclusions of the research to participants who so request. The REC must therefore have access to elements
p.000019: enabling it to ensure that the researchers have defined a publication policy, that they have discussed the matter
p.000019: with all external promoters so that they are not prevented from publishing the findings owing to contractual
p.000019: obligations. A reasonable period of time for publication is acceptable, in not order to adversely affect a
p.000019: patent application. However, this argument should not constitute a pretext for the unlimited retention of the
p.000019: findings.
p.000019: Particular concerns have been expressed regarding the publication of research findings on potential new
p.000019: treatments, biased notably owing to the concealment of ‘unfavourable’ findings. To overcome this practice and
p.000019: ensure that the findings are published, researchers should register all research projects before they begin in a
p.000019: register that is accessible to the public. The members of the REC can encourage this effort at transparency by making
p.000019: this registration a condition for their positive opinion regarding the ethical acceptability of the research
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000004: opinion until the findings are published.
p.000004: c. The issue of the publication of all the findings of research must be tackled at European level,
p.000004: for example in the context of the revision of European Directive 2001/20/EC relating to the implementation of
p.000004: good clinical practice in the conduct of clinical trials on medicinal products for human use.
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004:
p.000004: Final version
p.000005: 5
p.000005:
p.000005: 1. Registration and publication
p.000005: In its opinion No 133, the Advisory Committee on Bioethics considered the ethical problem raised by human
p.000005: experimentation.
p.000005: The issue tackled here is the need for the prospective registration of all clinical trials4 carried out
p.000005: on human subjects and the widest possible publication of their findings in order to prevent the underreporting of
p.000005: scientific discoveries. This relates to the problem of publication bias.
p.000005:
p.000005: 1.1. Underreporting of research findings
p.000005: Research findings may or may not be statistically significant. The classification of findings as positive or negative,
p.000005: favourable or unfavourable, important or of no interest in itself involves interpretation.5 Findings will usually
p.000005: be considered to be positive when they confirm the research assumption set out before the clinical trial: a new
p.000005: medicinal product put to trial, for example, is statistically more significant than the comparator
p.000005: (placebo or standard treatment). 6 Whatever the result, whether it is statistically significant or not, the extent
p.000005: of any differences found should also be examined.
p.000005:
p.000005: When the classification of statistically significant or insignificant findings as 'positive', 'negative' or
p.000005: 'of no interest’ influences their dissemination, underreporting or a publication bias regarding findings may occur.
p.000005: For instance, when positive findings concerning the efficacy of a new medicinal product are disseminated more
p.000005: widely than findings that are less positive or of no interest, this may give rise to an overvaluation of
p.000005: the efficacy of this medicinal product.7
p.000005: NIHR 2010 report
p.000005:
p.000005: In the context of its Health Technology Assessment Programme, in February 2010 the National Institute for Health
p.000005: Research (United Kingdom) published a study report entitled "Dissemination and publication of research
p.000005: findings: an updated review of related biases".
p.000005:
p.000005: As the title indicates, this report is an update of an initial report8 published in July 2000 which concluded in
p.000005: particular that despite the uncertainty surrounding the extent, the orientation and the impact of publication
p.000005: bias, it seems reasonable to conclude that studies
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005:
p.000005: 3 Opinion No 13:
p.000005: www.health.belgium.be/eportal/Healthcare/Consultativebodies/Commitees/Bioethics/Opinions/index.htm?&fodnlan g=fr
p.000005: 4 Broad definition of clinical trial, see also preliminary consideration.
p.000005: 5 Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al. (2010), “Dissemination and publication of research
...
Orphaned Trigger Words
p.000021: Moreover, the same directive aims to limit the premature interruption of scientific research projects (Article 3) to
p.000021: the extent that, in the context of these projects, trial subjects have already been subjected to experimental
p.000021: interventions.
p.000021: Or, to take the terms used by the CCMO in its 2010 annual report (p. 42): (free translation) “The directive aims to
p.000021: monitor the interest of the publication of research findings and prevent the premature ending of research for
p.000021: non-medical-scientific reasons.
p.000021: In fact, in this case, the trial subjects included until then could have taken part in clinical research for
p.000021: nothing.”67
p.000021: It may be concluded that the Netherlands are pioneers and are ahead of European initiatives and developments. Whereas
p.000021: the public was able to consult the basic data of research protocols relating to medical-scientific
p.000021: research (‘WMO’ act- medisch-wetenschappelijk onderzoek) from 2009 (https://ToetsingOnline.ccmo.nl), this
p.000021: possibility has only existed for research protocols included in the EudraCT database since 22 March 2011. It should
p.000021: also be pointed out in this context that the scope of application of the Dutch act is wider than that of European
p.000021: Directive 2001/20/EC, in which respect it is in line with the Belgian act. To date, no results have been included in
p.000021: the ToetsingOnline public register, but in the future, the CCMO does intend to record a summary. (See Annex 1, C.).
p.000021:
p.000021: The CCMO thus aims to achieve transparency both for medical-scientific research and for its (ethical) assessment.68
p.000021:
p.000021: Some conclusions
p.000021:
p.000021: The initiatives taken both by the Council of Europe and the Dutch CCMO show a trend towards granting
p.000021: medical ethics committees the power, when approving protocols, to assess the reasonable nature of the publication
p.000021: policy for research findings. The MECs should also be able to follow up the publication of research findings.
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021: 67 Original version:
p.000021: “De richtlijn beoogt het bewaken van het belang van openbaarmaking van de onderzoeksresultaten en het
p.000021: voorkomen van voortijdige beëindiging van onderzoek om niet-medisch-wetenschappelijke redenen. Dit kan immers tot
p.000021: gevolg hebben dat tot dan toe geïncludeerde proefpersonen voor niets hebben deelgenomen aan een klinisch
p.000021: onderzoek.”
p.000021: 68 CCMO annual report 2010: summary p. 6.
p.000021:
p.000021: Final version
p.000022: 22
p.000022:
p.000022: 3. GENERAL POINT OF VIEW AND RECOMMENDATIONS
p.000022: 3.1. Context
p.000022: Publication bias or the underreporting of research findings – especially those that are negative – is a
p.000022: complex problem that involves various stakeholders.
p.000022: Several initiatives have been developed over the past decade that aim to promote the transparency and
p.000022: hence the integrity of scientific research.
p.000022: The public registers used for the prospective registration of protocols offer the possibility of following up the
p.000022: implementation of clinical trials and observing/researching the findings. The pharmaceutical industry is
p.000022: admittedly reluctant to communicate information from protocols concerning the early phases of research. This may,
p.000022: indeed, be information that is sensitive in terms of competition.
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| access to information | Access to information |
| authority | Relationship to Authority |
| drug | Drug Usage |
| healthy volunteers | Healthy People |
| helsinki | declaration of helsinki |
| illness | Physically Disabled |
| influence | Drug Usage |
| job | Occupation |
| opinion | philosophical differences/differences of opinion |
| oviedo | oviedo |
| party | political affiliation |
| placebo | participants in a control group |
| political | political affiliation |
| poor | Economic/Poverty |
| property | Property Ownership |
| single | Marital Status |
| threat | Threat of Stigma |
| union | Trade Union Membership |
| volunteers | Healthy People |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| drug | ['influence'] |
| healthy volunteers | ['volunteers'] |
| influence | ['drug'] |
| party | ['political'] |
| political | ['party'] |
| volunteers | ['healthyXvolunteers'] |
Trigger Words
developing
ethics
justice
protect
protection
risk
sensitive
Applicable Type / Vulnerability / Indicator Overlay for this Input