Re: Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency
Recently, two very articulate opinions about a new medication for the treatment of alcohol dependence (nalmefene) were published in the BMJ. In the first review, Spence referred to nalmefene as “bad medicine”1; in the second letter, Braillon accused the European Medicines Agency of a “junk evaluation” of nalmefene.2 In this response, we address the arguments that were used in these communications to the readership of the BMJ.
In his review, Spence erroneously talks about nalmefene as a medication approved for alcohol abuse, while in fact the indication is alcohol dependence not responding to a brief intervention. Furthermore, Spence mentions that nalmefene was added to extensive additional counseling, while in fact patients in the study only received short sessions (10-15 minutes) of compliance and motivation enhancing support from their physicians, which is very close to standard clinical management and very different from “extensive counseling”.
Dr. Spence also refers to the “dark art of subgroup analysis”, but fails to mention that the results from the total group analyses were very similar to those of the subgroup analysis.1-3 Moreover, the subgroup analysis was clearly marked as secondary analysis performed not to improve outcome results, but to make the findings more relevant for routine clinical practice, where patients who reduce their drinking in response to a brief intervention and patients with low levels of alcohol use do not receive pharmacological treatment.
Dr. Spence is also not satisfied with the reported benefits of nalmefene in the targeted subgroup.3 Although he admits that the reductions in alcohol use resulted in objective improvements of liver function parameters, he would like to see larger effect size. We agree with him that the effects are modest, but the benefits are clinically relevant and of the same magnitude as many other registered drugs for the treatment of psychiatric and somatic diseases.6 Moreover, since there is no placebo condition in normal clinical practice, the reduction of 60-70% heavy drinking days in patient treated with nalmefene + compliance and motivation enhancement will result in substantial reductions in alcohol-related related morbidity and mortality.
Finally, Dr. Spence raises doubt about the (projected) cost-effectiveness of nalmefene when compared to naltrexone and counseling. In his criticism he ignores the fact that nalmefene and naltrexone have a different biochemical profile and that nalmefene is indicated only for those patients that do not respond to (brief) counseling.
The letter of Dr. Braillon makes strong statements on even less informed grounds.
First, he incorrectly states that authorization of nalmefene by the European Medicines Agency (EMA) was granted on a subgroup analysis and that the EMA did not have access to the raw data: all available data were presented to the EMA, including all ITT analyses of all randomized patients and the subgroup analysis of patients that are most likely to be treated with nalmefene in routine clinical practice.
Second, Dr. Braillon regrets the presence of missing data. However, missing data are the reality in the treatment of chronic disorders and should be handled in the best way possible, i.e. by ITT analyses using the last observation carried forward (LOCF) complemented by a series of sensitivity analyses using different assumptions for the imputation of missing data. Such analyses were performed and the results consistently showed that nalmefene is indeed an effective medication in the reduction of alcohol use in patients with alcohol dependence.1-3, 7
Third, and similar to Dr. Spence, Dr. Braillon feels that the endpoints that were used are poorly defined and non-reliable. However, the self-reported alcohol outcomes that were used were obtained using a state-of-the art, validated procedure (Time Line Follow Back).8 Moreover, even if these measures would have been unreliable (and every measure is unreliable to a certain extent), the reported results are an underestimation of the real effect and the real effect of nalmefene would be larger than the one reported in the studies. In addition, nalmefene was not only beneficial in terms of self-reported drinking reductions, but also in terms of objective liver function improvements, in expert ratings of clinical improvement, and in quality of life.
Finally, Dr. Braillon, suggests that previous experiences with nalmefene were not taken into account by the EMA decision to grant a license for nalmefene. However, all information, including all available information on nalmefene studies preceding the Lundbeck program, were disclosed to the EMA.
In short, none of the critical points raised by Dr. Spence and Dr. Braillon can be sustained against a serious reality check and we therefore conclude that their comments represent a seriously biased evaluation of a meticulous test program of a medication that may be helpful for many patients currently not receiving (adequate) treatment because they want to reduce their drinking but do not wish or do not feel able to reach total abstinence.
Wim van den Brink, MD PhD, Professor of Psychiatry and Addiction, Academic Medical Center University of Amsterdam, The Netherlands
Karl Mann, MD PhD, Professor of Psychiatry, University of Mannheim, Germany
Antoni Gual, MD PhD, Director Addictions Unit Clinic Hospital of Barcelona, Spain
Henri-Jean Aubin, Professor of Psychiatry and Addiction Medicine Université Paris-Sud, Paris, France
1 Spence D. Bad medicine: nalmefene in alcohol misuse. BMJ. 2014 Feb 14;348:g1531.
2 Braillon A. Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency. BMJ. 2014 Mar 10;348:g2017.
3. Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013 Apr 15;73(8):706-13.
4 Gual A, He Y, Torup L, van den Brink W, Mann K; ESENSE 2 Study Group. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013 Nov;23(11):1432-42.
5. van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol. 2013 Sep-Oct;48(5):570-8.
6. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry. 2012 Feb;200(2):97-106.
7. van den Brink W; Sørensen P; Torup L; Mann K; Gual A, SENSE Study Group. Long-term efficacy, tolerability, and safety of nalmefene as-needed in patients with alcohol dependence: A 1-year, randomised controlled study. J Psychopharmacol (in press)
8. Maisto SA, Sobell LC, Cooper AM, Sobell MB. Comparison of two techniques to obtain retrospective reports of drinking behavior from alcohol abusers. Addict Behav. 1982;7(1):33-8.
Competing interests: Wim van den Brink was the primary investigator (PI) of the 12 month safety and efficacy study of nalmefene (SENSE study), Karl Mann was the PI of the first 6 month efficacy study of nalmefene (ESENSE 1 study) and Antoni Gual was the PI of the second 6 month efficacy study of nalmefene (ESENSE 2 study). Wim van den Brink, Karl Mann, Antoni Gual and Henri-Jean Aubin were responsible for the subgroup analysis of the pooled data of the SENSE 1 and SENSE 2 study. Wim van den Brink, Karl Mann, Antoni Gual and Henri-Jean Aubin received honoraria and speakers fees from Lundbeck and are consultants to Lundbeck.