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Routinedatenbasierte Untersuchungen Zum Off-Label-Use in Der Ambulanten Versorgung

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Routinedatenbasierte Untersuchungen Zum Off-Label-Use in Der Ambulanten Versorgung Routinedatenbasierte Untersuchungen zum Off-Label-Use in der ambulanten Versorgung Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften - Dr. rer. nat.- Universität Bremen Fachbereich Human- und Gesundheitswissenschaften vorgelegt von Michael Dörks Bremen, im Juni 2013 Leibniz-Institut für Präventionsforschung und Epidemiologie - BIPS GmbH Danksagung Diese Dissertation sowie die hiermit in Verbindung stehenden Publikationen wären ohne die Anregungen und Unterstützung meiner Familie, meiner Freunde und vieler Kolleginnen und Kollegen nicht möglich gewesen. Ihnen möchte ich an dieser Stelle danken. Mein besonderer Dank gilt Frau Prof. Dr. Edeltraut Garbe, die diese Arbeit in vielerlei Hinsicht erst ermöglichte. Großer Dank gilt weiterhin Herrn Prof. Dr. Hajo Zeeb und Herrn PD Dr. Falk Hoffmann für die Bereitschaft zur Erstellung der Gutachten. Erstgutachter: Prof. Dr. med. Hajo Zeeb, M.Sc. Zweitgutachter: PD Dr. P.H. Falk Hoffmann, MPH Datum der Disputation: 01.11.2013 Inhaltsverzeichnis 1 Einleitung 2 2 Off-Label-Use 5 2.1 Definition von Off-Label-Use .................. 5 2.2 Bedeutung des Off-Label-Use im Spannungsfeld von Leistungs- erbringung, Gesetzeslage und medizinischem Fortschritt ................. 7 2.3 Off-Label-Use in der Pädiatrie ................. 9 2.4 Off-Label-Use in der Onkologie ................ 11 3 Die German Pharmacoepidemiological Research Database (Ge- PaRD) und ihre Nutzung zur Untersuchung des Off-Label-Use 13 3.1 Beschreibung von GePaRD ................... 14 3.2 Nutzung von Sozialdaten für die Forschung .......... 18 3.3 Untersuchung des Off-Label-Use ................ 19 4 Beispiele eigener Studien zur routinedatenbasierten Untersuchung des Off-Label-Use in der ambulanten Versorgung 21 4.1 Treatment of paediatric epilepsy in Germany: antiepileptic drug utilisation in children and adolescents with a focus on new antiepileptic drugs ..................... 21 4.2 Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population- based cohort study ....................... 24 4.3 Database study of lenalidomide (RevlimidR ) in Germany: monitoring off-label-use .................... 27 5 Diskussion 30 5.1 Datengrundlage ......................... 30 5.2 Off-Label-Use .......................... 36 I 6 Fazit und Ausblick 39 Literaturverzeichnis 40 A Abstract 51 B Eidesstattliche Erklärung 52 C Manuskripte 53 C.1 Treatment of paediatric epilepsy in Germany: antiepileptic drug utilisation in children and adolescents with a focus on new antiepileptic drugs ..................... 53 C.2 Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population- based cohort study ....................... 63 C.3 Database Study of Lenalidomide (RevlimidR ) in Germany: Monitoring Off-Label Use ................... 72 II Abbildungsverzeichnis 3.1 Datenfluss im deutschen Gesundheitswesen .......... 14 3.2 Aufbau von GePaRD ...................... 15 3.3 Verknüpfung von Analysedatensatz und pharmazeutischer Re- ferenzdatenbank über die Pharmazentralnummer ....... 17 3.4 Die fünf Ebenen des anatomisch-therapeutisch-chemischen Arz- neimittelklassifikationssystems am Beispiel von Fluoxetin . 18 4.1 Strukturen der alten Antiepileptika ............... 22 4.2 Strukturen der neuen Antiepileptika/Strukturanalogität zu γ- Aminobuttersäure (GABA) ................... 23 4.3 Strukturen von Thalidomid und Lenalidomid ......... 28 4.4 T-Rezept zur Verodnung von thalidomid- oder lenalidomid- haltigen Arzneimitteln ..................... 29 5.1 Altersverteilung männlicher Versicherter in GePaRD im Ver- gleich zur männlichen bundesdeutschen Bevölkerung im Jahr 2005 ............................... 35 5.2 Altersverteilung weiblicher Versicherter in GePaRD im Ver- gleich zur weiblichen bundesdeutschen Bevölkerung im Jahr 2005 ............................... 35 III Tabellenverzeichnis 2.1 Altersabhängige Veränderungen pharmakokinetischer Parame- ter bei Neugeborenen und Kindern im Vergleich zum Erwach- senen .............................. 10 4.1 Molekulare Zielstrukturen und pharmakokinetische Interak- tion mit Isoenzymen des Cytochrom P450 (CYP) alter und neuer Antiepileptika ....................... 24 4.2 Häufigkeit unerwünschter Wirkungen von Antidepressiva . 26 IV Abkürzungsverzeichnis AED Antiepileptikum AMG Arzneimittelgesetz ApBetrO Apothekenbetriebsordnung ATC-Code Anatomisch-therapeutisch-chemischer Code ATD Antidepressivum AWMF Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. BÄK Bundesärztekammer BfArM Bundesinstitut für Arzneimittel und Medizinprodukte BMBF Bundesministerium für Bildung und Forschung BMG Bundesministerium für Gesundheit BSG Bundessozialgericht BVA Bundesversicherungsamt CYP Cytochrom P450 DDD Defined Daily Dose DIMDI Deutsches Institut für Medizinische Dokumentation und Information DKG Deutsche Krankenhausgesellschaft EBM einheitlicher Bewertungsmaßstab eGK elektronische Gesundheitskarte EMA European Medicines Agency eRezept elektronisches Rezept FDA Food and Drug Administration GABA γ-Aminobuttersäure (englisch: gamma-aminobutyric acid) G-BA Gemeinsamer Bundesausschuss GePaRD German Pharmacoepidemiological Research Database GKV gesetzliche Krankenversicherung ICD International Classification of Diseases ICPM Internationale Klassifikation der Prozeduren in der Medizin IMiDs Immunomodulatory Drugs KAKJ Kommission für Arzneimittel für Kinder und Jugendliche KBV Kassenärztliche Bundesvereinigung MDK Medizinischer Dienst der Krankenversicherung MDS myelodysplastisches Syndrom NSAR nichtsteroidales Antirheumatikum OADs andere Antidepressiva OLG Oberlandesgericht OPS Operationen- und Prozedurenschlüssel V OTC-Arzneimittel Over the counter-Arzneimittel PKV private Krankenversicherung PZN Pharmazentralnummer RMP Risikomanagementplan SGB Sozialgesetzbuch SNRI Serotonin-Noradrenalin-Wiederaufnahmehemmer SSRI Selektiver Serotonin-Wiederaufnahmehemmer TCA trizyklisches Antidepressivum UAW unerwünschte Arzneimittelwirkung WHO World Health Organization WIdO Wissenschaftliches Institut der Ortskrankenkassen VI Zusammenfassung In vielen medizinischen Fachgebieten, insbesondere in der Kin- derheilkunde, der Psychiatrie und in der Onkologie, wird ein Groß- teil der Arzneimittel Off-Label eingesetzt. Als Off-Label-Use be- zeichnet man die zulassungsüberschreitende Anwendung von Arz- neimitteln, insbesondere den Gebrauch außerhalb der angezeig- ten Anwendungsgebiete oder der Patientengruppe, für die sie von den zuständigen Behörden zugelassen worden sind. Ein Problem des Off-Label-Use sind mögliche Implikationen für die Arznei- mittelsicherheit aufgrund von unerwünschten Arzneimittelwirkun- gen. Es gibt nur wenige systematische Untersuchungen zum Aus- maß des Off-Label-Use in der ambulanten Versorgung in diesen medizinischen Disziplinen in Deutschland. Die Nutzung von Routinedaten der gesetzlichen Krankenver- sicherungen (GKVen) für die Versorgungsforschung und Pharma- koepidemiologie hat in den letzten Jahren kontinuierlich zuge- nommen. Pharmakoepidemiologische Arzneimittelutilisationsstu- dien basierend auf Routinedaten ermöglichen diesbezüglich po- pulationsbasierte Untersuchungen des Arzneimittelgebrauchs ein- schließlich des Off-Label-Use von Arzneimitteln. Basierend auf Routinedaten der GKVen umfasst die vorliegende Dissertation Untersuchungen zum ambulanten Off-Label-Use von Antidepres- siva und Antiepileptika in der Pädiatrie und zum ambulanten Off- Label-Use des onkologischen Arzneistoffes Lenalidomid im Rah- men eines behördlich geforderten Risikomanagementplans. Die Untersuchung des Off-Label-Use im Rahmen von Arz- neimittelutilisationsstudien schließt eine Lücke in der Erforschung von Arzneimitteln nach Marktzulassung. Routinedaten stellen auf- grund fehlender Beeinflussung des Verschreibungsverhaltens ei- ne wichtige Datenquelle für die Untersuchung des Off-Label-Use dar, insbesondere bei Patientengruppen, die in klinischen Studien oftmals unterrepräsentiert sind. 1 Kapitel 1 Einleitung Die Zulassung eines Arzneimittels nach § 25 des Arzneimittelgesetzes (AMG) soll die Qualität, Wirksamkeit und Unbedenklichkeit eines Arzneimittels ge- währleisten. Ausschlaggebend für die Notwendigkeit der Etablierung eines Zulassungsverfahrens für Arzneimittel war in Deutschland die sogenannte ConterganR -Katastrophe, bei der mehr als 10.000 Kinder mit Gliedmaßen- und weiteren Fehlbildungen aufgrund der Anwendung des Arzneimittels Con- terganR mit dem Wirkstoff Thalidomid (α-Phthalimidoglutarimid) während der Schwangerschaft geboren wurden [1] [2]. Als Folge der ConterganR - Affäre wurde im Jahr 1976 das Gesetz über den Verkehr mit Arzneimitteln verabschiedet und trat 1978 in Kraft. Seitdem wurde es durch vielfältige Än- derungen an den jeweils aktuellen Stand der wissenschaftlichen Erkenntnis sowie der europäischen Entwicklung angepasst [2]. Thalidomid und seine Derivate, so genannte IMiDsR (Immunomodulatory Drugs) wie Lenalido- mid, werden heute aufgrund ihrer antiangiogenetischen und immunmodula- torischen Effekte in der Krebstherapie eingesetzt [3] [4] [5] [6]. Als Off-Label-Use bezeichnet man die nicht zulassungskonforme Anwen- dung von Arzneimitteln, insbesondere den Gebrauch außerhalb der angezeig- ten Anwendungsgebiete oder der Patientengruppe, für die sie von den Arznei- mittelbehörden zugelassen worden sind. Insbesondere in der Onkologie, Neu- rologie, Psychiatrie sowie der Kinderheilkunde ist der Off-Label-Use weit- verbreitet und wird häufig als unverzichtbarer Bestandteil der
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