BMJ 2014;348:g2017 doi: 10.1136/bmj.g2017 (Published 10 March 2014)
Page 1 of 2
Letters
LETTERS NALMEFENE IN ALCOHOL MISUSE
Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency Alain Braillon public health doctor Northern Hospital, 80000 Amiens, France
“If you torture the data long enough, it will confess.” Ronald Coase. Spence claims that nalmefene in alcohol misuse is bad medicine.1 In my opinion it is junk evaluation by the European Medicines Agency.
Firstly, the authorisation was granted on subgroup analysis of two randomised controlled studies of six months’ duration.2 This subgroup comprised only a quarter of the patients and at six months up to half of the data were missing in the nalmefene group (table⇓).3 This is not intention to treat analysis. In this very small subgroup too many data are missing and too many patients were lost to follow-up. Access to the raw data is warranted. Secondly, the authors of the subgroup analysis disclosed strong conflicts of interests.2 I note that one, Henri-Jean Aubin, the chairman of the French Association of Alcohology, will chair a symposium sponsored by Lundeck at the association’s next meeting.4
Thirdly, the European Medicines Agency accepted a reduction in drinking at six months as an endpoint, whereas the US Food and Drug Administration does not. The FDA is right, this surrogate endpoint has not been validated. The European Medicines Agency found this surrogate endpoint only in a ”white paper” jointly released by the first author of the subgroup analysis, Wim van den Brink, who is a beneficiary of
honorariums from Lundbeck.5 Moreover, the endpoints in the nalmefene trials were obtained from patient reports, a non-reliable method.6
Lastly, in 1998 Contral Pharma tried to develop nalmefene for alcohol related problems but in 2003 nalmefene did not meet phase III clinical endpoints with statistical significance. These data must be disclosed too. Competing interests: None declared. 1 2
3
4 5 6
Spence D. Bad medicine: nalmefene in alcohol misuse. BMJ 2014;348:g1531. (14 February.) Van den Brink W, Aubin H-J, 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;48:570-8. Van den Brink W, Aubin H-J, 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;48:570-8; supplementary data. http://alcalc.oxfordjournals.org/content/suppl/2013/ 06/14/agt061.DC1/agt061supp.pdf. French Association of Alcohology. De la prevention au soin meeting, Paris, 19-21 March 2014. www.sfalcoologie.asso.fr/download/SFA2014mars-Prog.pdf. European Medicines Agency. Assessment report Selincro (nalmefene). EMA/78844/2013. 13 December 2012. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_ assessment_report/human/002583/WC500140326.pdf. Wetterling T, Dibbelt L, Wetterling G, Göder R, Wurst F, Margraf M, et al. Ethyl glucuronide (EtG): better than breathalyser or self-reports to detect covert short-term relapses into drinking. Alcohol Alcohol 2014;49:51-4.
Cite this as: BMJ 2014;348:g2017 © BMJ Publishing Group Ltd 2014
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2017 doi: 10.1136/bmj.g2017 (Published 10 March 2014)
Page 2 of 2
LETTERS
Table Table 1| Numbers of participants in the main trial and subgroup analysis Analysis Main trial
23
Placebo Nalmefene 658
664
Month 0
167
171
Month 6
114
85
Month 0
155
148
Month 6
111
103
Subgroup analysis Heavy drinking days:
Daily consumption of alcohol:
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Letters
LETTERS NALMEFENE IN ALCOHOL MISUSE
Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency Alain Braillon public health doctor Northern Hospital, 80000 Amiens, France
“If you torture the data long enough, it will confess.” Ronald Coase. Spence claims that nalmefene in alcohol misuse is bad medicine.1 In my opinion it is junk evaluation by the European Medicines Agency.
Firstly, the authorisation was granted on subgroup analysis of two randomised controlled studies of six months’ duration.2 This subgroup comprised only a quarter of the patients and at six months up to half of the data were missing in the nalmefene group (table⇓).3 This is not intention to treat analysis. In this very small subgroup too many data are missing and too many patients were lost to follow-up. Access to the raw data is warranted. Secondly, the authors of the subgroup analysis disclosed strong conflicts of interests.2 I note that one, Henri-Jean Aubin, the chairman of the French Association of Alcohology, will chair a symposium sponsored by Lundeck at the association’s next meeting.4
Thirdly, the European Medicines Agency accepted a reduction in drinking at six months as an endpoint, whereas the US Food and Drug Administration does not. The FDA is right, this surrogate endpoint has not been validated. The European Medicines Agency found this surrogate endpoint only in a ”white paper” jointly released by the first author of the subgroup analysis, Wim van den Brink, who is a beneficiary of
honorariums from Lundbeck.5 Moreover, the endpoints in the nalmefene trials were obtained from patient reports, a non-reliable method.6
Lastly, in 1998 Contral Pharma tried to develop nalmefene for alcohol related problems but in 2003 nalmefene did not meet phase III clinical endpoints with statistical significance. These data must be disclosed too. Competing interests: None declared. 1 2
3
4 5 6
Spence D. Bad medicine: nalmefene in alcohol misuse. BMJ 2014;348:g1531. (14 February.) Van den Brink W, Aubin H-J, 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;48:570-8. Van den Brink W, Aubin H-J, 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;48:570-8; supplementary data. http://alcalc.oxfordjournals.org/content/suppl/2013/ 06/14/agt061.DC1/agt061supp.pdf. French Association of Alcohology. De la prevention au soin meeting, Paris, 19-21 March 2014. www.sfalcoologie.asso.fr/download/SFA2014mars-Prog.pdf. European Medicines Agency. Assessment report Selincro (nalmefene). EMA/78844/2013. 13 December 2012. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_ assessment_report/human/002583/WC500140326.pdf. Wetterling T, Dibbelt L, Wetterling G, Göder R, Wurst F, Margraf M, et al. Ethyl glucuronide (EtG): better than breathalyser or self-reports to detect covert short-term relapses into drinking. Alcohol Alcohol 2014;49:51-4.
Cite this as: BMJ 2014;348:g2017 © BMJ Publishing Group Ltd 2014
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2017 doi: 10.1136/bmj.g2017 (Published 10 March 2014)
Page 2 of 2
LETTERS
Table Table 1| Numbers of participants in the main trial and subgroup analysis Analysis Main trial
23
Placebo Nalmefene 658
664
Month 0
167
171
Month 6
114
85
Month 0
155
148
Month 6
111
103
Subgroup analysis Heavy drinking days:
Daily consumption of alcohol:
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
