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Aktuelle Neurologie 2015; 42(06): 323-334
DOI: 10.1055/s-0035-1552653
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Bestimmung des Nutzens und des Zusatznutzens von Antiepileptika: eine kritische Übersicht

Assessing the Benefit and the Added Benefit of Antiepileptic Drugs – a Critical Review
D. Schmidt
1   Arbeitsgruppe Epilepsieforschung Berlin
,
R. Surges
2   Klinik für Epileptologie, Universität Bonn
,
T. W. May
3   Gesellschaft für Epilepsieforschung, Koordinierungszentrum für Klinische Studien in der Epileptologie (KSE), Epilepsie-Zentrum Bethel, Bielefeld
,
C. E. Elger
2   Klinik für Epileptologie, Universität Bonn
› Institutsangaben
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Publikationsverlauf

Publikationsdatum:
10. Juni 2015 (online)

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Zusammenfassung

Obwohl die Erfassung der Anfallsfrequenz vor und während der Behandlung die Grundlage zur Beurteilung der Wirksamkeit neuer Antiepileptika (AED) ist, zeigen alle bisher durchgeführten Untersuchungen, dass vom Patienten geführte Anfallskalender unzuverlässig sind und für die adäquate Bewertung von Interventionen neue methodische Ansätze gewählt werden müssen. Die traditionelle Gabe von Placebo in der klinischen Prüfung des Nutzens von neuen Zusatz-AEDs ist wegen der zahlreichen selektiven Einflussfaktoren auf die anfallshemmende Wirkung von Placebo methodisch unzuverlässig, falls nicht alle Einflussfaktoren kontrolliert werden. Die Placebogabe ist ethisch zweifelhaft, weil den Teilnehmern während der Studiendauer möglicherweise wirksame AEDs vorenthalten werden und dies ist angesichts eines erhöhten SUDEP-Risikos unter Placebo nicht unbedenklich. Für die klinische Praxis sind zudem die Ergebnisse direkt vergleichender Studien („Head-to-Head-Studien“), in denen AED miteinander bzw. gegen ein Standard-AED getestet werden, aussagekräftiger als ein Vergleich mit Placebo. Daher sollten Zulassungsbehörden Studien der Wirksamkeit und Unbedenklichkeit im Vergleich zur Standardtherapie zum Zeitpunkt der Zulassung fordern, in denen mindestens die Nichtunterlegenheit gegenüber der Standardtherapie nachgewiesen wird. Die frühe Nutzenbewertung fragt ebenfalls nach dem Zusatznutzen im Vergleich zu den bislang verfügbaren Therapieoptionen. Placebokontrollierte Untersuchungen ohne konkurrente Vergleichstherapie sind nicht geeignet zur direkten Bestimmung des Zusatznutzens. Ein internationaler Konsens über Studiendesigns zum Nachweis des Zusatznutzens von Antiepileptika ist dringend notwendig.

Abstract

Although measuring the frequency of seizures prior to and during treatment is the basis for assessing the efficacy of new antiepileptic drugs (AED), all studies show that patients' seizure diaries are unreliable. Therefore, we need new methods to adequately assess interventions in epilepsy. The traditional use of placebos as controls to assess the anti-seizure efficacy of new AEDs in add-on trials is methodologically flawed unless the numerous factors that influence the efficacy of placebo can be fully controlled. The use of placebo is ethically flawed because study participants are denied treatment with potentially more effective AEDs for the duration of the trial and cannot be considered safe because denying AED treatment is associated with an increased risk of sudden unexpected death in epilepsy (SUDEP) in those on placebo. Furthermore, results of direct comparison of head-to-head studies of new AEDs with standard AEDs are clinically much more valuable than seizure versus placebo. This is why regulatory authorities should ask for studies of efficacy and safety of new drugs as compared to standard treatment at the time of entering the market that show at least their non-inferiority to standard therapy. The early evaluation of added benefit also asks for evidence of added value versus the available treatment options. Placebo-controlled trials without concurrent control with standard care are not suitable for direct assessment of added value. An international consensus on trial designs to assess the added value of new AEDs is urgently needed..

Schlüsselwörter

Antiepileptika - Zusatznutzen - AMNOG - Placebo - Nocebo - SUDEP - Zulassungsstudien - Antiepileptikaentwicklung

Keywords

antiepileptic drugs - added value - AMNOG - placebo - nocebo - SUDEP - placebo response - clinical development of antiepileptic drugs - market authorization studies
 

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