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Studien Bei Seltenen Erkrankungen IQWiG-Berichte – Nr. 241 Bewertung und Auswertung von Studien bei seltenen Erkrankungen Rapid Report Auftrag: MB13 -01 Version: 1.0 Stand: 05.09.2014 Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Impressum Herausgeber: Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen Thema: Bewertung und Auswertung von Studien bei seltenen Erkrankungen Auftraggeber: Bundesministerium für Gesundheit (BMG) Datum des Auftrags: 10.12.2013 Interne Auftragsnummer: MB13-01 Anschrift des Herausgebers: Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen Im Mediapark 8 (KölnTurm) 50670 Köln Tel.: +49 (0)221 – 35685-0 Fax: +49 (0)221 – 35685-1 E-Mail: [email protected] Internet: www.iqwig.de ISSN: 1864-2500 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - i - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Externes Review des Rapid Reports . Norbert Benda (Bundesinstitut für Arzneimittel und Medizinprodukte) Dieser Rapid Report wurde einem externen Review unterzogen. Das IQWiG dankt dem externen Reviewer für seine Mitarbeit am Projekt. Der Reviewer war jedoch nicht in die Erstellung des Rapid Reports eingebunden. Daher geben einzelne Passagen und Schlussfolgerungen des Rapid Reports nicht notwendigerweise die Meinung des Reviewers wieder. Die Selbstangaben des externen Reviewers zu potenziellen Interessenkonflikten sind in Anhang B dargestellt. Es wurden keine Interessenkonflikte festgestellt, die die fachliche Unabhängigkeit im Hinblick auf eine Bearbeitung des vorliegenden Auftrags gefährden. Für die Inhalte des Berichts ist allein das IQWiG verantwortlich. Mitarbeiter des IQWiG1: . Ulrich Grouven . Ralf Bender . Ulrike Lampert . Stefan Lange . Stefan Sauerland . Ulrich Siering . Volker Vervölgyi 1 Aufgrund gesetzlicher Datenschutzbestimmungen haben Mitarbeiter das Recht, ihrer Namensnennung nicht zuzustimmen. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - ii - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Inhaltsverzeichnis Seite Tabellenverzeichnis .................................................................................................................. v Abbildungsverzeichnis ............................................................................................................ vi Abkürzungsverzeichnis .......................................................................................................... vii Kurzfassung ........................................................................................................................... viii 1 Hintergrund ....................................................................................................................... 1 2 Ziele der Untersuchung ..................................................................................................... 3 3 Projektbearbeitung ............................................................................................................ 4 3.1 Zeitlicher Verlauf des Projekts .................................................................................. 4 4 Methoden ............................................................................................................................ 5 4.1 Methodische Expertise ................................................................................................ 5 4.1.1 Gegenwärtige Rahmenbedingungen und Problemstellung .................................... 5 4.1.2 Methodische Aspekte bei der Bewertung und Auswertung von Studien ............... 5 4.2 Empirische Untersuchung zur Studiengrundlage für die Zulassung von Orphan Drugs in Europa ........................................................................................... 5 4.2.1 Informationsbeschaffung ........................................................................................ 5 4.2.2 Informationssynthese .............................................................................................. 6 4.2.3 Informationsanalyse ............................................................................................... 7 5 Ergebnisse ........................................................................................................................... 8 5.1 Methodische Expertise ................................................................................................ 8 5.1.1 Grundlegende methodische Aspekte bei der Bewertung und Auswertung von Studien .................................................................................................................... 8 5.1.2 Barrieren gegen randomisierte Studien ................................................................ 11 5.1.3 Situation bei seltenen Erkrankungen .................................................................... 13 5.1.4 Design-Vorschläge für randomisierte Therapiestudien bei seltenen Erkrankungen ....................................................................................................... 14 5.1.4.1 Varianzreduzierende Verfahren und Designs ................................................. 15 5.1.4.2 Sequenzielle und adaptive Designs ................................................................ 16 5.1.4.3 Bayesʼsche Verfahren ..................................................................................... 17 5.1.4.4 Designs, bei denen alle Patienten (auch) die Prüfintervention erhalten ......... 19 5.1.4.5 Sonstige Designs ............................................................................................. 21 5.1.5 Ergebnissicherheit nicht randomisierter Studien .................................................. 22 5.1.6 Empfehlungen ...................................................................................................... 24 5.1.6.1 Politische Vorgaben ........................................................................................ 25 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - iii - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 5.1.6.2 Strukturen ....................................................................................................... 25 5.1.6.3 Effizienz .......................................................................................................... 26 5.1.6.4 Kompromisse bei der Aussagesicherheit ........................................................ 27 5.2 Ergebnisse der empirischen Untersuchung zur Studiengrundlage für die Zulassung von Orphan Drugs in Europa ................................................................ 28 5.2.1 Ergebnisse der Informationsbeschaffung und resultierender Publikationspool ... 28 5.2.2 Ergebnisse der Informationssynthese und Informationsanalyse .......................... 28 6 Diskussion ......................................................................................................................... 36 7 Fazit ................................................................................................................................... 40 8 Literatur ........................................................................................................................... 41 Anhang A – Extraktionstabellen zur Auswertung der Zulassungsstudien zu Orphan Drugs ....................................................................................................................................... 48 Anhang B – Offenlegung potenzieller Interessenkonflikte des externen Reviewers ........ 85 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - iv - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Tabellenverzeichnis Seite Tabelle 1: Zusammenhang zwischen Einschränkung der Zulassung und Einbezug von RCT-Daten ............................................................................................................................... 29 Tabelle 2: Anzahl der Hauptstudien pro Arzneimittel ............................................................. 30 Tabelle 3: Studiencharakteristika (Arzneimittelebene) ............................................................ 31 Tabelle 4: Studiencharakteristika der RCT (Studienebene) ..................................................... 33 Tabelle 5: Verwendete statistische Methoden in den RCTs (Studienebene) ........................... 35 Tabelle 6: Orphan Drugs – Charakteristika .............................................................................. 48 Tabelle 7: Methodische Aspekte der Zulassungsstudien zu Orphan Drugs (Studienebene) .... 55 Tabelle 8: Übersicht der Zulassungsstudien zu Orphan Drugs (Arzneimittelebene) ............... 79 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - v - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Abbildungsverzeichnis Seite Abbildung 1: Anteil der Orphan Drugs, die auf Basis von RCTs zugelassen wurden, im zeitlichen Verlauf (N = 85) ...................................................................................................... 29 Abbildung 2: Anteil der Zulassungen, bei denen patientenrelevante Endpunkte (primär oder sekundär) ausgewertet wurden, im zeitlichen Verlauf (N = 79) ...................................... 32 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) - vi - Rapid Report MB13-01 Version 1.0 Studien bei seltenen Erkrankungen 05.09.2014 Abkürzungsverzeichnis Abkürzung Bedeutung ACHSE Allianz Chronischer Seltener Erkrankungen BfArM Bundesinstitut
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