Demotes

WMA Satellite Meeting during the 11th World Congress of Bioethics:
Thinking ahead – The future of the Declaration of Helsinki
June 26th 2012, Rotterdam, The Netherlands
ECRIN proposals for amendments to the
Declaration of Helsinki: ethics committees,
transparency, and choice of comparator
Rita Banzi, Vittorio Bertelé, Xavier Carné, Jacques Demotes-Mainard,
Silvio Garattini, Christian Gluud
Jacques Demotes
jacques.demotes@inserm.fr
www.ecrin.org
ECRIN, an infrastructure supporting
international cooperation in clinical
trials
A pan-European, distributed
infrastructure providing coordinated
services to multinational clinical
research in Europe:
 access to patients and to expertise
throughout Europe
 despite the fragmentation of health,
legislative and funding systems
 support to investigators and sponsors
in multinational studies
 to make Europe a single area for
clinical research
Suggestions to improve the
Declaration of Helsinki
 Ethics Committees
1 – training of ethics committee members (§15)
2 – independence of the research ethics committees (§15)
 Transparency
3 – protocol, raw data, recruitment, incentives (§30)
 Trial design
4 – methodology based on systematic reviews (§12).
5 – use of placebo (§32) based on medical grounds
6 – ethical dimension of non-inferiority and equivalence trials
 Wording
7 – ‘participants’ instead of ‘subjects’
Ethics Committees:
training and independence
1 – training of ethics committee members (§15)
required to ensure credibility and reproducibility of their
decisions, a critical issue in multinational trials.
2 – independence of the research ethics committees (§15)
“This committee must be independent of the researcher,
the sponsor and any other undue influence”.
challenged when linked to an institution that is also be the
initiator or sponsor of a clinical trial.
Transparency
3 – Authors, editors and publishers all have ethical obligations with regard to the
publication of the results of research. Authors have a duty to make publicly available
the results of their research on human subjects and are accountable for the
completeness and accuracy of their reports. They should adhere to accepted
guidelines for ethical reporting. Negative and inconclusive as well as positive results
should be published or otherwise made publicly available. Sources of funding,
institutional affiliations and conflicts of interest should be declared in the
publication… (§30)
– 20-item registration
– Publication of results
– Registration of full protocol and amendments
– Access to raw, anonymised data Hrynaszkiewicz and Altman Trials 2009,10:17
– optimal use of data (repository ?)
– credibility and quality of the trial
– Recruitment performance Dal Re et al. PLoS Medicine 2011, 8:e1001149
– Incentives
ECRIN Scientific Board:
Acceptance criteria
1 – Multicentre trial run in at least two European countries.
2 – Rules for transparency:
– Commitment to register the trial in a public register before inclusion of the
first participant, for example on www.clinicaltrials.gov.
– Commitment to publish results irrespective of findings.
– Commitment to make raw anonymised data sets available to the scientific
community upon legitimate request to the sponsor or principal investigator
once the trial is completed.
– Declaration of conflicts of interest.
3 – Rationale based on up-to-date systematic reviews of clinical data or, where not
possible, of preclinical data on the experimental intervention and comparator.
4 – Clinical relevance and/or marked impact on public health.
5 – Suitable overall trial design appropriate to the clinical question, including for
example:
– Selection of an appropriate and justified experimental intervention and
comparator.
– Adequate sample size with supporting calculation.
– Relevant patient population (inclusion and exclusion criteria), setting, and
duration of treatment and follow up.
– Outcome measures for efficacy and safety with clinically meaningful benefit
for the patient.
Design: the clinical relevance should
prevail over statistical considerations
Clinical relevance is the goal,
statistics is an instrument
4 – methodology based on
systematic reviews (§12).
Medical research involving human
subjects must conform to generally
accepted scientific principles, be
based on a thorough knowledge of
the scientific literature, other
relevant sources of information, and
adequate laboratory and, as
appropriate, animal
experimentation.
Design: the clinical relevance should
prevail over statistical considerations
5 – use of placebo (§32) based on medical grounds:
the improper use of placebo harms the participants
Bertelé et al. J Clin Pharmacol. 2012, 68:877-9
The benefits, risks, burdens and effectiveness of a new intervention must be tested
against those of the best current proven intervention, except in the following
circumstances:
– The use of placebo, or no treatment, is acceptable in studies where no current
proven intervention exists; or
– Where for compelling and scientifically sound methodological reasons the use of
placebo is necessary to determine the efficacy or safety of an intervention and the
patients who receive placebo or no treatment will not be subject to any risk of
serious or irreversible harm. Extreme care must be taken to avoid abuse of this
option.
Design: the clinical relevance should
prevail over statistical considerations
6 – ethical dimension of non-inferiority and equivalence trials:
Garattini & Bertelé, Lancet 2007, 370:1875-7
participants take risks without expected benefits
 explicitly mentioned in the informed consent sheet
Ferran.Torres@uab.es 10
0
Lower equivalence
boundary
Upper equivalence
boundary
Treatment more effective -><- Treatment less effective 2 3 4 5 Treatment-Control 1 Superiority Ferran.Torres@uab.es 11 0 Lower equivalence boundary Upper equivalence boundary Treatment more effective -><- Treatment less effective 2 3 4 5 Treatment-Control 1 Equivalence Ferran.Torres@uab.es 12 0 Lower equivalence boundary Upper equivalence boundary Treatment more effective -><- Treatment less effective 2 3 4 5 Treatment-Control 1 Non-Inferiority Ferran.Torres@uab.es 13 0 Lower equivalence boundary Upper equivalence boundary Statistical Superiority Non-inferiority Equivalence Inferiority Treatment-Control Statistically and Clinically superiority Statistically and Clinically Superiority Non relevant/negative effect relevant effect Wording 7 – ‘participants’ instead of ‘subjects’ or ‘cases’ Thank you !