Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`British Journal of Clinical
`Pharmacology
`Commentary
`
`DOI:10.1111/bcp.12176
`
`Meta-analyses of antiepileptic drugs for refractory
`partial (focal) epilepsy: an observation
`
`Martin J. Brodie
`
`Epilepsy Unit, Western Infirmary, Glasgow, UK
`
`There are now a handful of published meta-analyses sur-
`rounding the efficacy and tolerability of, particularly, the
`newer antiepileptic drugs (AEDs) as adjunctive treatment
`for patients with refractory focal (partial) seizures [1–4]. All
`have included numerous published studies with largely
`similar designs and have come to largely similar nonspe-
`cific conclusions. These complicated and time-consuming
`exercises have, in the main, not contributed usefully to eve-
`ryday clinical practice in helping to refine the choice of
`treatment for patients with drug-resistant focal epilepsies.
`There are two main reasons for their lack of clinical
`value: firstly,
`this patient population is notoriously
`pharmacoresistant; and, secondly, the vast majority of the
`included studies were placebo controlled and, to make
`matters worse, many were regulatory trials, which were
`designed, undertaken and completed prior to the launch
`of the drug under investigation.
`Despite the introduction of 14 AEDs in Europe and the
`USA over the last two decades,the general feeling from the
`neurological community has been one of disappointment
`[5]. The main reason for this conclusion is the pattern of
`response in this patient population to AED therapy. There
`are now a number of published outcome studies in newly
`diagnosed epilepsy [6]. More than 50% of adult patients
`will become seizure free with their first drug either imme-
`diately or after a short delay to allow the diagnosis to be
`accepted and/or for the dosing to be optimized [7]. A
`further 10% will respond to their second AED or first com-
`bination. The third treatment schedule will
`identify a
`further 3% with a good outcome. Thereafter, an increas-
`ingly shrinking percentage will become seizure free with
`subsequent drug regimens, with only a handful being con-
`trolled on AED combinations. This last population com-
`prises the majority of patients taking part in the studies
`included in these meta-analyses. After 10 years of treat-
`ment, only around 50% of this patient population will still
`be seizure free [7].
`the second drug
`the failure of
`Outcomes after
`schedule are particularly disappointing in patients with
`focal
`(partial) seizures [7].
`Indeed, the definition of
`
`pharmacoresistant epilepsy published by the ad hoc task
`force of the International League against Epilepsy is ‘failure
`of adequate trial of two tolerated, appropriately chosen
`and used AED schedules (whether as monotherapies or in
`combination) to achieve sustained seizure freedom’ [8].
`Patients with focal (partial) epilepsy, who are likely to
`be recruited into placebo-controlled trials, are almost
`all pharmacoresistant, and very few will subsequently
`become seizure free for any useful length of time.
`The second major concern with these meta-analyses in
`patients with refractory focal (partial) seizures is the inclu-
`sion of a high percentage of placebo-controlled trials.
`These patients are highly selected, and the trials are
`subject to a broad range of exclusion criteria. Most of the
`studies are of short duration and employ a variety of fixed
`drug doses. This unpromising situation is further exacer-
`bated by the inclusion in these analyses of a large number
`of placebo-controlled trials undertaken for regulatory pur-
`poses.These patient populations, in particular, are not rep-
`resentative of everyday clinical practice. The dose for each
`patient in the majority of these studies is chosen randomly
`and is preceded by a fixed and often overly fast titration
`schedule. All will already be established on high doses of
`other AEDs. There is little leeway for reducing the dose of
`the test drug if the patient does not tolerate the randomly
`assigned arbitrary amount, nor can the doses of existing
`AEDs be adjusted should side-effects develop.
`Not surprisingly, very few of these patients become
`seizure free even for the short duration, usually 3 or 4
`months, of the trial [9]. The primary end-point for these
`studies, therefore, is the percentage reduction in seizure
`numbers for the Food and Drug Administration (FDA) in
`the USA and responder rate (percentage of patients dem-
`onstrating a 50% or greater seizure reduction) for the Euro-
`pean Medicines Agency (EMA), both vs. baseline seizure
`frequency. These outcomes have very little clinical rel-
`evance for epilepsy patients, whose quality of life is not
`improved by a percentage seizure reduction, but only by
`attaining sustained seizure freedom [10]. Neither does
`their short duration predict long-term efficacy. This trial
`
`630 / Br J Clin Pharmacol
`
`/ 76:5 / 630–631
`
`© 2013 The British Pharmacological Society
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`methodology has its drawbacks also in detecting side-
`effects, because recruited patients are already taking
`sometimes one, usually two and occasionally three other
`AEDs, often at high dosage.
`What, therefore, can be taken from these complex,
`costly and time-consuming studies that is relevant for eve-
`ryday clinical practice? The short answer is not very much.
`This brings me back to the systemic review and network
`meta-analysis of Pritesh Bodalia and co-workers [4]. Their
`first conclusion was the need for long-term comparative
`trials. This is obvious and arguably reasonable, if almost
`impossible to undertake and likely to be extremely expen-
`sive. One of the many problems with such a design
`is the complex and numerous pharmacokinetic and
`pharmacodynamic interactions among the individual
`AEDs that would complicate dosing, produce side-effects
`and interfere with honest efficacy outcomes. Their second
`conclusion was that conventional random-effects meta-
`analysis showed that all the studied AEDs were superior
`in efficacy to placebo, but did not permit distinctions
`between the drugs on the basis of efficacy and tolerability.
`This again is hardly surprising and not clinically useful.
`If, as have other authors, Bodalia and his team had
`settled for these broad conclusions, all would have been
`well, although their paper would be rather a boring read.
`However, Bodalia et al. were tempted to apply a sophisti-
`cated Bayesian network meta-analysis comparing short-
`term efficacy and tolerability of the individual AEDs, which
`rather artificially suggested benefit for some of these
`drugs over others. This last analysis and its clinically naive
`conclusions have substantially reduced the value of the
`exercise.The critical letter from Gaetano Zaccara and his 11
`clinical colleagues rightly points out the importance of
`including all studies with an appropriate design. Dosing of
`the AEDs needed to be relevant to everyday clinical usage.
`Regulatory trials that were undertaken before the drug
`was used in clinical practice often included higher doses
`than those that were subsequently found to be useful in
`the clinic. Lastly, Zaccara et al. pointed out that ‘this sort of
`complex statistical process should always be checked
`against actual clinical experience’. Are they saying that
`poor-quality evidence is less valuable than good clinical
`practice? I hope so!
`
`Competing Interests
`
`There are no competing interests to declare.
`
`Commentary
`
`2 Costa J, Faraleira F, Ascencau R, Borges M, Sampaio C,
`Vaz-Carnero A. Clinical comparability of the new and
`epileptic drugs in refractory partial epilepsy: a systematic
`review and meta-analysis. Epilepsia 2011; 52: 1280–91.
`
`3 Rheims S, Perucca E, Cucherat M, Ryvlin P. Factors
`determining response to antiepileptic drugs in randomized
`controlled trials. A systematic review and meta-analysis.
`Epilepsia 2011; 52: 219–33.
`
`4 Bodalia PN, Grosso AM, Sofat R, MacAllister J, Smeeth L,
`Dhillon S, Casas J-P, Wonderung D, Hingorani AD.
`Comparative efficacy and tolerability of antiepileptic drugs
`for refractory focal epilepsy. Systematic review and network
`meta-analysis reveals the need for comparator trials. Br J Clin
`Pharmacol 2013; 76: 649–67.
`
`5 Löscher W, Schmidt D. Modern antiepileptic drug
`development has failed to deliver: ways out of the current
`dilemma. Epilepsia 2011; 52: 657–78.
`
`6 Mohanraj R, Brodie MJ. Early predictors of outcome in newly
`diagnosed epilepsy. Seizure 2013; 22: 333–44.
`
`7 Brodie MJ, Barry SJE, Bamagous GA, Norrie J, Kwan P.
`Patterns of treatment response in newly diagnosed epilepsy.
`Neurology 2012; 78: 1548–54.
`
`8 Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA,
`Mathern G, Moshé SL, Perucca E, Wiebe S, French J.
`Definition of drug resistant epilepsy: consensus proposal by
`the ad hoc Task Force of the ILAE Commission on
`Therapeutic Strategies. Epilepsia 2010; 51: 1069–77.
`
`9 Gazzola DM, Baller LJ, French JA. Seizure-free outcomes in
`randomized add-on trials of new antiepileptic drugs.
`Epilepsia 2007; 48: 1303–7.
`
`10 Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C,
`Galimberti CP, Gatti G, La Neve A, Muscas G, Specchio LM,
`Striano S, Perucca E, on behalf of the SOPHIE study group.
`Determinants of health-related quality of life in
`pharmacoresistant epilepsy: results from a large multicenter
`study of consecutively enrolled patients using validated
`quantitative assessments. Epilepsia 2011; 52: 2181–91.
`
`RECEIVED
`17 May 2013
`
`ACCEPTED
`24 May 2013
`
`ACCEPTED ARTICLE PUBLISHED ONLINE
`6 June 2013
`
`REFERENCES
`
`1 Beyenburg S, Stavern K, Schmidt D. Placebo-controlled
`efficacy of modern antiepileptic drugs for refractory
`epilepsy: systematic review and meta-analysis. Epilepsia
`2010; 51: 7–26.
`
`CORRESPONDENCE
`Professor Martin J. Brodie MBChB, MD, FRCP, Epilepsy Unit,
`Western Infirmary, Glasgow G11 6NT, UK.
`Tel.: +44 141 211 2534
`Fax: +44 141 211 2072
`E-mail: mjb2k@clinmed.gla.ac.uk
`
`Br J Clin Pharmacol
`
`/ 76:5 / 631
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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