Evaluation in alcohol use disorders – insights from the nalmefene experience

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Nalmefene was the first treatment approved by the European Medicines Agency for reducing alcohol consumption in adult patients with alcohol dependence. It is often presented as a paradigm shift in therapeutics, but major issues limit the interpretation of the evidence supporting its use. The randomised trials submitted provided no evidence of harm reduction, the differences on consumption outcomes were of questionable clinical relevance, the target population was defined a posteriori and the drug was compared to a placebo although naltrexone was already used off-label. No post-approval randomised study is currently designed to clearly address these issues. In addition, nalmefene trials have been uncritically cited, even in guidelines. This experience reveals weaknesses in drug evaluations in alcohol dependence, which call for changes. We propose to dispense with alcohol consumption as a surrogate outcome, to consider comparative effectiveness issues, and to recommend randomised post-approval studies in case of controversial approval.

On 13 December 2012, nalmefene, an opioid antagonist, was approved by the European Medicines Agency (EMA) for the reduction of alcohol consumption in adult patients with alcohol dependence, a high drinking-risk level, no physical withdrawal symptoms and not requiring immediate detoxification. It is the first treatment in this indication when the usual aim in alcohol dependence is abstinence from drinking. The approval [1] was based on the results of two phase III randomised controlled trials (RCTs) lasting 6 months [2, 3], one lasting 1 year [4], and four earlier RCTs including dose–response studies (two of these were unpublished studies) [5, 6]. Some additional supporting evidence was also presented, including pooled subgroup analyses [7] and further analyses on the expected harm reduction (alcohol-related physical health outcomes, injuries or social consequences) based on the literature data and on modelling from the clinical trial data [8, 9]. Despite this body of evidence, the approval was contested, with some disagreement between and within the different health authorities. For instance, six members of the Committee for Medicinal Products for Human Use at the EMA expressed divergent positions in an appendix to the assessment report. The National Institute for Care and Excellence (NICE) in the UK initially recommended nalmefene as a possible treatment for alcohol dependence [10] but subsequently distanced itself from this earlier advice [11]. The German and Swedish health authorities simply stated that there was no added benefit from nalmefene [12, 13].

The RCTs performed have thus failed to demonstrate an unequivocal benefit for the drug, despite the fact that, from a regulatory perspective, this should be their principal aim.

We propose here to examine the evidence that led to the approval of nalmefene and to understand why studies were not unequivocal in this specific case, how their results were integrated into the health authority decisions and how the controversy spread in the medical literature. Our final purpose is to propose relevant changes concerning therapeutic evaluation in the field of alcohol dependence.

Autoři: Florian Naudet ^1*; Clément Palpacuer ²; Rémy Boussageon ³; Bruno Laviolle ²
Působiště autorů: Meta-Research Innovation Center at Stanford (METRICS), Stanford University, 1070 Arastradero Road, Palo Alto, CA 94304, USA. ¹; INSERM Centre d’Investigation Clinique 1414, Centre Hospitalier Universitaire de Rennes, Rennes, France. 3Département de Médecine Générale, Faculté de Médecine de Poitiers, Poitiers, France. ²
Vyšlo v časopise: BMC Medicine 2016, 14:119
Kategorie: Correspondence
prolekare.web.journal.doi_sk: https://doi.org/10.1186/s12916-016-0664-9

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The electronic version of this article is the complete one and can be found online at: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0664-9

Souhrn

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