Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2113 - 1/5
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2113 - 2/5
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2113 - 3/5
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`British Journal of Clinical
`Pharmacology
`Letter to the Editors
`
`DOI:10.1111/bcp.12175
`
`Network meta-analysis and the comparison of
`efficacy and tolerability of anti-epileptic drugs for
`treatment of refractory focal epilepsy
`
`Gaetano Zaccara,1 Sanjay M. Sisodiya,2 Fabio Giovannelli,1 Matthew C. Walker,2
`Dominic C. Heaney,2 Heather Angus-Leppan,3 Tim Wehner,2 Sofia H. Eriksson,2
`Rebecca Liu,3 Fergus Rugg-Gunn,2 Simon D. Shorvon2 & Josemir W. Sander2
`
`1Unit of Neurology, San Giovanni di Dio Hospital, Firenze, Italy, 2NIHR University College London Hospitals Biomedical Research
`Centre, UCL Institute of Neurology, London & Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter and 3Royal Free
`Hospital, London, United Kingdom
`
`We read with interest the recent paper on network meta-
`analysis [1] in which efficacy and tolerability of selected
`anti-epileptic drugs in people with refractory focal epi-
`lepsy were compared.
`Whilst network meta-analysis may be a powerful tool,
`the validity of the results must depend on the selection of
`studies included. In this respect, we are curious about
`several methodological points. The authors include some
`studies but not others that are of the same nature. The
`authors deem as appropriate doses those that most expe-
`rienced epilepsy clinicians would consider unusual and the
`results that emerge would be considered misleading by
`most experienced epilepsy clinicians.
`Only one of the four drugs the authors suggest have
`efficacy and tolerability in focal epilepsies would be
`accepted as such by experienced epilepsy clinicians. Their
`recommendation of vigabatrin in this category is most
`surprising, given the significant adverse effects asso-
`ciated with its use. The paper illustrates the importance of
`ensuring that
`the results of any complex statistical
`process should always be checked against actual clinical
`experience. The authors selected for comparison only
`people receiving doses of the target drugs which they
`deemed appropriate. Despite the authors’ claim that they
`chose the selected doses based on their clinical experi-
`ence, the choice seems arbitrary, is out of keeping with
`clinical experience and is not based on any stated evi-
`dence. For instance, only someone with little clinical expe-
`rience of oxcarbazepine would consider doses over
`1800 mg day−1 as appropriate. The dose of 2400 mg is
`poorly tolerated by most people. It is also unlikely that
`many people would tolerate doses of topiramate over
`300 mg day−1.
`
`Several relevant studies were not included, without
`clear explanation. For instance, a key lacosamide study [2]
`was not
`included. The same apply for studies with
`topiramate [3] and levetiracetam [4]. Two relevant
`lamotrigine studies [5, 6] were also excluded. One could
`suggest that these were excluded as they were crossover
`studies, but then other crossover studies were included,
`such as a levetiracetam study [7]. It is imperative that con-
`sistent criteria are applied for study selection if this type of
`analysis is to be meaningful.
`The authors conclude that in their mixed-treatment
`network meta-analysis, levetiracetam, vigabatrin, sodium
`valproate and gabapentin emerge as the anti-epileptic
`drugs with the best combination of short term efficacy and
`tolerability. As experienced epilepsy clinicians having seen
`many thousands of patients, we do not consider that
`valproate and gabapentin should be considered as first
`line anti-epileptic drugs for people with focal epilepsy,
`whilst any epilepsy clinician would know that the risk of
`visual field loss with vigabatrin is far too high to contem-
`plate its regular use. The authors’ recommendation on
`valproate appears to emanate from one old study compar-
`ing vigabatrin with valproate, in which a small number of
`people with epilepsy not controlled by carbamazepine
`were given either valproate or vigabatrin [8]. It is not clear
`why better quality data [9] were omitted from the analysis.
`For these reasons, the conclusions cannot be consid-
`ered particularly helpful.The need for answers to the ques-
`tions the authors set out
`to address remains. One
`important thing to remember is that epilepsy, a symptom-
`complex, is not a single disease but a collection of many
`different conditions for which the current clinical trials
`paradigm is completely inappropriate [10, 11].
`
`© 2013 The British Pharmacological Society
`
`Br J Clin Pharmacol
`
`/ 76:5 / 827–828 / 827
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2113 - 4/5
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`

`
`Letter to the Editors
`
`Competing Interests
`
`All authors have completed the Unified Competing Inter-
`est form at http://www.icmje.org/coi_disclosure.pdf (avail-
`able on request from the corresponding author). All
`authors declare no support from any organization for the
`submitted work.
`GZ has received speaker’s or consultancy fees from
`Jansen-Cilag, UCB Pharma, GSK, Sanofi-Aventi and Eisai
`which are involved in the manufacture of antiepileptic
`drugs; SMS has received speaker’s or consulting fees from
`UCB Pharma, Eisai and GSK; his institution has received
`research support
`from UCB Pharma, GSK and Eisai;
`MCW received speaker’s fees from Eisai, UCB Pharma,
`Viropharma and GSK; DCH has received speaker’s or con-
`sultancy fees from UCB Pharma and Eisai; SHE has received
`speaker’s fee from UCB Pharma; TW has received travel
`support from UCB Pharma and GSK; FRG has received
`speaker’s fee from Eisai, UCB Pharma and GSK; SDS has
`received speaker’s or consultancy fees from UCB, Eisai, GSK,
`Bial, SAGE, Lundbeck; JWS has received speaker’s or con-
`sulting fees from UCB Pharma and GSK; his institution has
`received research support from UCB Pharma, GSK and
`Eisai.
`All authors declare no other relationships or activities
`that could appear to have influenced the submitted work.
`
`REFERENCES
`
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`8 Brodie MJ, Mumford JP. Double-blind substitution of
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`9 Willmore LJ, Shu V, Wallin B. Efficacy and safety of add-on
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`
`RECEIVED
`8 March 2013
`
`ACCEPTED
`15 March 2013
`
`ACCEPTED ARTICLE PUBLISHED ONLINE
`6 June 2013
`
`CORRESPONDENCE
`Dr Gaetano Zaccara MD, Unit of Neurology, San Giovanni di Dio
`Hospital, Via Di Torregalli 3, Azienda Sanitaria di Firenze, 50143
`Firenze, Italy.
`Tel.: +39 05 5719 2476
`Fax: +39 05 5719 2280
`E-mail: gaetano.zaccara@asf.toscana.it
`
`828 / 76:5 / Br J Clin Pharmacol
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2113 - 5/5