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DOI: 10.1055/s-0042-116950
Möglichkeiten und Herausforderungen der Extrapolation bei Biosimilars
Opportunities and challenges of extrapolation for biosimilarsPublication History
29 August 2016
06 September 2016
Publication Date:
06 October 2016 (online)
Zusammenfassung
Obwohl sich die bisher in der Europäischen Union zugelassenen Biosimilars als sicher und effektiv erwiesen haben, werden deren Zulassungsanforderungen weiterhin kontrovers in der Ärzteschaft diskutiert. Insbesondere die Extrapolation zu Indikationen des Originators ohne eigene klinische Daten für das Biosimilar ist umstritten. Konzeptuell entstammt die Entwicklung von Biosimilars derjenigen von Generika. Wegen ihrer Komplexität und inhärenten Variabilität sind für Biosimilars jedoch wesentlich mehr Daten notwendig, um Vergleichbarkeit mit dem Originator (dem Referenzarzneimittel) zu zeigen, als für die üblicherweise kleinmolekularen Generika. Biosimilars erhöhen den Wettbewerb und helfen, die Kosten der Gesundheitssysteme einzuschränken und den Zugang von Patienten zu den wertvollen Therapien mit Biologika zu verbessern. Die Entwicklung eines Biosimilars ist aber aufwendig und langwierig und verlangt großes biotechnologisches Know-how. Grundlage ist die umfassende strukturelle und funktionelle Charakterisierung von Biosimilar und Referenzprodukt und deren Vergleich mit geeigneten und sensitiven Methoden. Das klinische Entwicklungsprogramm ist verkürzt und maßgeschneidert, um Restunsicherheiten zu adressieren und die klinische Vergleichbarkeit zu bestätigen. Die Extrapolation von Daten zu anderen Indikationen des Referenzprodukts ist der größte Kostenvorteil der Biosimilar-Entwicklung, muss aber immer wissenschaftlich begründet und ggf. durch weitere Daten substanziiert werden. Die wissenschaftlichen Prinzipien der Vergleichsstudien für ein Biosimilar folgen denen einer Änderung im Herstellungsprozess für ein bereits zugelassenes Biologikum. In beiden Fällen werden verschiedene Versionen einer biologischen Substanz verglichen und die klinische Relevanz von detektierten Unterschieden bewertet. Zulassungsbehörden haben jahrzehntelange Erfahrung in der Beurteilung von Änderungen im Herstellungsprozess, die sie nun auf Biosimilars anwenden können. Für die Zulassung eines Biosimilars und der Extrapolation von Daten wird die Gesamtheit der Evidenz aus allen Vergleichsstudien berücksichtigt, wie dies auch für das erste Infliximab-Biosimilar der Fall war.
Abstract
Although biosimilars approved in the European Union have proved to be safe and efficacious, their licensing requirements continue to be disputed by medical professionals. In particular, extrapolation to indications of the originator without one’s own clinical data of the biosimilar is controversial. Conceptually, the development of biosimilars is derived from that of generics. However, due to their complexity and inherent variability, considerably more data are necessary for biosimilars to demonstrate comparability with the originator (the reference product) than for the usually low-molecular generics. Biosimilars increase competition and help contain healthcare, and they improve access for patients to valuable treatments with biologicals. However, biosimilar development is a laborious and lengthy process and requires major biotechnological know-how. The basis is comprehensive, structural, and functional characterization of the biosimilar and reference product as well as their comparison with suitable and sensitive methods. The clinical development programme is reduced and tailored to address remaining uncertainties and to confirm comparable clinical performance. Extrapolation of data to other indications of the reference product is the greatest cost advantage of biosimilar development, but must always be scientifically justified and, if necessary, substantiated by further data. The scientific principles underlying the comparability exercise for a biosimilar are the same as those applied to a change in the manufacturing process of an already licensed biological. In both cases, different versions of a biological substance are compared and the clinical relevance of observed differences is assessed. Competent authorities do have decades of experience in evaluating changes in the manufacturing process, which they can now apply to biosimilars. For approval of a biosimilar and extrapolation of data, the totality of the evidence from the complete comparability exercise is considered, as has been the case for the first biosimilar infliximab.
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