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Seite 1 von 4 Sichere Medizinprodukte besser überwachen Im Zusammenhang mit Brustimplantaten des französischen Herstellers PIP (Poly Implant Prothèse) ist Kritik an der Sicherheit von Medizinprodukten aufgekommen. Der Hersteller hatte Prüfbehörden getäuscht und illegal minderwertiges Industriesilikon verarbeitet, was im Verdacht steht, gesundheitsgefährdend zu sein. Gegen ihn wurde Strafanzeige erstattet. Die Sicherheit der in Deutschland verwendeten Medizinprodukte ist nach Ansicht der Branchenverbände der Medizinprodukteindustrie durch eine Reihe aufeinander abge- stimmter Verordnungen und Gesetzen gegeben. Dazu gehören das am 1. Januar 1995 in Kraft getretene Medizinproduktegesetz (MPG) und die auf seiner Grundlage erlassenen Verordnungen, die die europäischen Richtlinien über aktive Implantate (90/385/EWG), über Medizinprodukte (93/42/EWG) und über In-vitro-Diagnostika (98/79/EG) in nationales Recht umsetzen. Es besteht zudem eine grundsätzlich gut funktionierende Marktüberwachung, die aber möglicherweise in diesem Fall nicht ausreichend befolgt wurde. Gleichwohl garantiert die Einhaltung der gesetzlichen Anforderungen den höchst möglichen Grad an Gesundheitsschutz, Leistungsfähigkeit und Sicherheit, also Qualität für Patienten, Anwender und andere Personen. Definition Medizinprodukte Medizinprodukte sind Instrumente, Apparate, Vorrichtungen, Software, Materialien oder chemische Substanzen und deren Zubereitungen, die ein Hersteller für die Anwendung am Menschen vorgesehen hat. Medizinprodukte werden zu Untersuchungen oder Behandlungen eingesetzt, sie sollen Krankheiten oder Behinderungen verhüten oder lindern. Medizinprodukte werden im Körper (z.B. Herzschrittmacher), am Körper (z.B. Sehhilfe) oder außerhalb des Körpers (Labortest) eingesetzt. Die Hauptwirkung der Medizinprodukte wird auf physikalischem Weg erzeugt, also mechanisch, elektrisch oder thermisch. Im Gegensatz dazu wirken die meisten Arzneimittel nach Verteilung im Körper pharmakologisch, immunologisch oder metabolisch. Zu den Medizinprodukten werden z.B. folgende Artikel gezählt: Verbandstoffe, Infusionsgeräte, Katheter, Herzschrittmacher, Hüft- und Knieprothesen, Sehhilfen, Gehhilfen, Implantate aller Art, Zahnersatz, Blutzuckermessgeräte, Röntgengeräte, EKG- Schreiber, Ultraschall-Diagnosegeräte, Kernspintomographen, Kondome, ärztliche Instrumente und Labordiagnostika. Aufgrund der Unterschiedlichkeit der Produkte und dem daraus resultierenden unterschiedlichen Risikopotenzial werden auch unterschiedlich hohe Anforderungen an sie gestellt. Seite 2 von 4 CE-Kennzeichnung als Zeichen für Qualität und Sicherheit Ohne CE-Kennzeichnung darf ein Medizinprodukt nicht auf den europäischen Markt und damit auch nicht auf den deutschen Markt gebracht werden. Mit der CE-Kennzeichnung dokumentiert der Hersteller, dass seine Medizinprodukte die europäischen Anforderungen erfüllen. Abhängig von der jeweiligen Risikoeinstufung des Produkts muss eine Prüfstelle ("Benannte Stelle") eingeschaltet werden, die zusätzlich als neutrale Auditier-, Zertifizier- und Prüfstelle fungiert. Dies kann beispielsweise der TÜV, Dekra usw. sein. Alle Benannten Stellen werden staatlich benannt und überwacht. Die Ansprüche, die eine CE-Kennzeichnung an die Qualität und Sicherheit von Medizinpro- dukten stellt, sind hoch. Sie werden auch nicht dadurch relativiert, dass CE-Kennzeich- nungen ebenfalls auf Aufzügen, Seilbahnen, Kinderspielzeug und Bügeleisen zu finden sind. Denn: Für Medizinprodukte gelten eigene produktspezifische Gesetzesvorgaben, um eine CE-Kennzeichnung aufbringen zu dürfen. Das heißt: Die Anforderungen für die CE- Kennzeichnung auf Medizinprodukten entsprechen nicht denen der CE-Kennzeichnung auf Spielzeug, sondern gehen weit über diese hinaus. Zusätzlich zur Sicherheit muss der Nachweis der Leistungsfähigkeit im Rahmen der klinischen Bewertung erbracht werden. Betreiben und Anwenden von Medizinprodukten Das Medizinproduktegesetz schreibt vor, dass alle Medizinprodukte nur dann betrieben oder angewendet werden dürfen, wenn sie keine Mängel aufweisen, durch die Patienten, Beschäftigte oder andere Personen gefährdet werden könnten. Dies gilt für die erste Inbetriebnahme ebenso wie für jede weitere Anwendung. Der Umgang mit Medizinprodukten darf nur dafür ausgebildeten Personen überlassen werden. Dies ist in der Medizinprodukte-Betreiberverordnung detailliert geregelt. So müssen nicht nur Medizinproduktebücher für die Dokumentation lückenlos geführt werden, sondern auch sicherheitstechnische Kontrollen regelmäßig nachgewiesen werden. Dass solche Kontrollen für die Patientensicherheit unverzichtbar sind, ist insbesondere bei lebenserhaltenden Geräten wie etwa Säuglingsinkubatoren oder maschinellen Beatmungsgeräten naheliegend. Dokumentations- und Instandhaltungspflichten Zum hohen Sicherheitsstandard von Medizinprodukten gehört auch die sorgfältige Dokumentation aller Vorgänge, um bei Fehlern oder Schäden die Anwendungs- und Vertriebswege nachvollziehen zu können. Die Betreiber von Medizinprodukten wie etwa Krankenhäuser und Arztpraxen müssen dafür sorgen, dass Wartung, Instandsetzung und hygienische Aufbereitung regelmäßig und von Fachleuten durchgeführt werden. So muss beispielsweise die hygienische Aufbereitung mit validierten Verfahren entsprechend dem Standard des Robert-Koch-Instituts und des Bundesinstituts für Arzneimittel und Medizinprodukte (BfArM) durchgeführt werden. Seite 3 von 4 Prüfpflichten Sicherheits- und messtechnische Kontrollen müssen ebenfalls regelmäßig nachgewiesen werden. So müssen bestimmte kritische Geräte, wie z.B. Beatmungsgeräte, mindestens alle zwei Jahre nach den anerkannten Regeln der Technik geprüft und die Prüfung dokumentiert werden. Meldepflichten Die Hersteller, Betreiber, Anwender und Händler eines Medizinprodukts sind verpflichtet, Vorkommnisse bzw. Produktzwischenfälle unverzüglich zu melden, um vorbeugend Gefahren abzuwehren. Die Erfassung, Bewertung und Abwehr von Risiken regelt die Medizinprodukte-Sicherheitsplanverordnung. Ein "meldepflichtiges Vorkommnis" ist definiert als eine Funktionsstörung, ein Ausfall, eine Änderung der Merkmale oder der Leistung, eine unsachgemäße Kennzeichnung oder Gebrauchsanweisung eines Medizinprodukts, die unmittelbar oder mittelbar zum Tod oder zu einer schwerwiegenden Verschlechterung des Gesundheitszustandes eines Patienten, eines Anwenders oder einer anderen Person geführt hat, geführt haben könnte oder führen könnte. Vorkommnisse sind sofort der zuständigen Bundesoberbehörde, dem Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) zu melden. Das BfArM bewertet das Risiko des Vorkommnisses. Hierzu macht der Hersteller in Zusammenarbeit mit dem BfArM Vorschläge zur Beseitigung des bestehenden Mangels. Zur Diskussion – Bewährtes System weiter verbessern Das europaweit geltende Medizinprodukterecht und seine Umsetzung hat sich seit über 15 Jahren bewährt. Durch das hochkriminelle Verhalten eines Einzelnen ist das europäische System der Marktzulassung und –überwachung von Medizinprodukten in Misskredit gebracht worden. Bei der Diskussion um eine Weiterentwicklung des aktuellen regulatorischen Systems sollte intensiv geprüft werden, wo und welche Maßnahmen geeignet sind, die Einhaltung der gesetzlichen Vorschriften über die Herstellung von Medizinprodukten hinaus noch besser überwachen zu können. Dadurch soll die Sicherheit des Patienten gestärkt und kriminelles Verhalten erschwert werden. So hätten schärfere Anforderungen für den Zugang von Medizinprodukten zum europäischen Markt den PIP-Fall nicht verhindern können, denn dort wurden Implantate mit medizinischem Silikon vorgelegt, die anschließend in krimineller Absicht gegen minderwertiges Industriesilikon ausgetauscht wurden. Seite 4 von 4 Das Bundesgesundheitsministerium hat 2011 in seiner vergleichenden Analyse der Zu- lassung von Arzneimitteln und Medizinprodukten gezeigt, dass die Schutzziele – ins- besondere die Patientensicherheit - identisch sind und lediglich auf unterschiedlichem Wege erreicht werden. Ein „staatliches Zulassungssystem“ für Medizinprodukte bietet kein Mehr an Patientensicherheit. Die Branchenverbände der Medizinprodukteindustrie schlagen für eine Stärkung der Patientensicherheit vor:  Verbesserung der Meldepflicht. Die Betreiber und Anwender von Medizinprodukten müssen Vorkommnisse bzw. Produktzwischenfälle entsprechend den Vorschriften melden, um Herstellern und Behörden die Möglichkeit zu geben, frühzeitig auf potenzielle Unregelmäßigkeiten reagieren zu können. Von entscheidender Bedeutung ist ein sorgfältiges Melden insbesondere durch Krankenhäuser und Arztpraxen. Meldungen sollen nicht fehlerhaftes Verhalten des medizinischen Personals oder anderer Personen anzeigen, sondern sich auf das Medizinprodukt beziehen. Dies dient der Qualitätsverbesserung eines Medizinproduktes und damit dem Schutz der Patienten. Die Branchenverbände der Medizinprodukteindustrie haben hierzu ein Informationsblatt erarbeitet, um die Betreiber und Anwender für die Bedeutung der Vorkommnismeldungen bzw. Produktzwischenfälle zu sensibilisieren (Anlage).  Unangemeldete Kontrollen im Markt. Das Medizinproduktegesetz erlaubt dies bereits heute. Bei begründeten Verdachtsfällen sollte dieses Instrument von den zuständigen Zulassungs- und/oder Überwachungsbehörden eingesetzt werden.  Ausstattung der Überwachungsbehörden. Für die Überwachung ist eine sachge- rechte personelle und materielle Ausstattung der Behörden sicher zu stellen.  Einheitliches Qualitätsniveau der Benannten Stellen. Die Sicherstellung eines einheitlichen Qualitätsniveaus aller akkreditierten Benannten Stellen ist bereits gesetzlich geregelt. Durch eine erneute Prüfung der Akkreditierung aller Benannten Stellen sollte ein europaweit einheitliches Niveau erreicht werden.  Sanktionen. Bei Verstoß gegen das Medizinproduktegesetz und seine Verordnungen müssen die gesetzlich vorgesehenen Bußgeld- und Strafsanktionen konsequent ange- wendet werden. Anlage Herausgeber: Branchenverbände der Medizinprodukteindustrie März 2012 Meldepflichten der Betreiber und Anwender von Medizinprodukten nach MPG und MPSV Das Medizinprodukte-Beobachtungs- und -Meldesystem ist ein wesentliches Element der Sicherheitsphilosophie für Medizinprodukte und hat zum Ziel, für einen wirksamen Schutz von Patienten, Anwendern und Dritten bei deren Anwendung zu sorgen. Zur Erreichung dieses Ziels müssen alle Beteiligten, darunter auch die Betreiber und Anwender von Medizinprodukten, gemäß den §§ 3 (2) und 5 (2) der Medizinprodukte- Sicherheitsplanverordnung (MPSV), Vorkommnisse unverzüglich an das BfArM melden. Vorkommnisse sind: 1. jede Funktionsstörung oder 2. jeder Ausfall und jede Änderung der Merkmale oder der Leistungen oder 3. jede Unsachgemäßheit der Kennzeichnung oder der Gebrauchsanweisung, die zum Tode oder zu einer schwerwiegenden Verschlechterung des Gesundheitszustandes einer Person geführt hat, geführt haben könnte oder führen könnte. Meldepflichtig sind alle Vorkommnisse, für die das Medizinprodukt (möglicherweise) ursächlich ist, z.B. bedingt durch einen Konstruktionsfehler, mangelhafte Gebrauchstauglichkeit oder ein Materialproblem, oder die auf fehlenden oder missverständlichen Angaben in der Produktkennzeichnung oder Gebrauchsanweisung beruhen. Als Betreiber und Anwender sind Sie ebenfalls gehalten, alle für die Aufklärung des Sachverhalts erforderlichen Unterlagen (z.B. Durchleuchtungsbilder, Implantations- und Nachsorgeprotokolle) sowie das/die betroffene/n Produkt/e für den Hersteller und ggf. die Behörde für Nachforschungen bereitzustellen. Wann muss gemeldet werden? Betreiber oder Anwender müssen Vorkommnisse im Zusammenhang mit dem Betrieb oder der Anwendung von Medizinprodukten „unverzüglich“, also „ohne schuldhaftes Zögern“, melden. An wen muss gemeldet werden? Die Meldung muss an das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) gerichtet werden: BfArM, Abt. 9 Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn Das aktuell gültige Meldeformular zur Meldung von Vorkommnissen durch Betreiber und Anwender finden Sie als Word-Dokument auf den Webseiten des BfArM unter: http://www.bfarm.de/DE/Medizinprodukte/form/mp_formulare_anwender.html Bei In-vitro-Diagnostika mit hohem Risiko ergeht die Meldung an das Paul-Ehrlich-Institut (PEI): http://www.pei.de/cln_227/nn_748690/DE/infos/pu/08-meldepflichten/meldepflichten-node.html?__nnn=true Empfehlung: Richten Sie Ihre Meldung zeitgleich - z. B. als Kopie der BfArM-Meldung - auch an den Hersteller des Medizinproduktes. Denn es ist die primäre Aufgabe des Herstellers, geeignete Maßnahmen zur Risikoabwehr zu ergreifen. Die Adresse des Herstellers finden Sie auf der Produkt- bzw. Verpackungskennzeichnung und/oder in der Gebrauchsanweisung. Wer ist Ansprechpartner in Industrie und Handel? Ansprechpartner sind die Medizinprodukteberater des Herstellers oder Fachhändlers vor Ort. Der Medizin- produkteberater ist verpflichtet, die ihm vorgetragenen Informationen schriftlich an die verantwortlichen Stellen (d.h. an den Medizinprodukte-Sicherheitsbeauftragten des Herstellers oder an den Geschäftsführer des Händlers) weiterzuleiten. Warum muss gemeldet werden? Durch die Auswertung gemeldeter Risiken bzw. Ereignisse und die schnelle Weitergabe der Informationen wird der Gesundheitsschutz verbessert. Damit tragen auch Sie dazu bei, dass sich eventuelle Probleme und Schäden nicht wiederholen oder verhindert werden. Meldungen sind keine Schuldzuweisungen oder Schuldeingeständnisse. Sie ziehen grundsätzlich keine Sanktionen nach sich. Daher unser Appell an Sie: Helfen Sie mit, den Schutz der Patienten zu verbessern. Melden Sie Vorkommnisse! Hrsg.: Arbeitsgruppe MPG der Industriefachverbände (AG MPG) http://www.bfarm.de/DE/Medizinprodukte/form/mp_formulare_anwender.html http://www.pei.de/cln_227/nn_748690/DE/infos/pu/08-meldepflichten/meldepflichten-node.html?__nnn=true

Der BAH war durch Herrn Dr. Guido Middeler (Hälsa Pharma GmbH, Lübeck) und durch den Vorsitzenden der AG Dental Herrn Walker (VITA Zahnfabrik H. Rauter GmbH & Co.KG, Bad Säckingen) sowie durch die BAH-Rechtsanwältin Dr. Angela Josewski vertreten. Im Zusammenhang mit Brustimplantaten des französischen Herstellers PIP (Poly Implant Prothèse) war in der jüngsten Vergangenheit Kritik an der Sicherheit von Medizinprodukten aufgekommen. Der Hersteller hatte Prüfbehörden getäuscht und illegal minderwertiges Industriesilikon verarbeitet, was im Verdacht steht, gesundheitsgefährdend zu sein. Da in Jahr 2012 darüber hinaus umfangreicher Änderungen im Rahmen der europäischen Medizinprodukterichtlinien in Vorbereitung sind, ist das auf dem New Approach (sog. neuer Ansatz) basierende Medizinprodukterecht ins Wanken geraten. Die hinter dem neuen Ansatz stehende Idee ist, dass dem Hersteller ein vergleichsweise hoher Grad an Eigenverantwortung zugesprochen wird und er die Produkte in enger Zusammenarbeit mit einer Benannten Stelle in den Verkehr bringt. Anders als bei den Arzneimitteln gibt es für die Medizinprodukte keine behördliche Zulassung und somit einen sehr schnellen Marktzugang für Produkte, die zum Teil sehr kurzen Innovationszyklen haben. Die fehlende Behördenbeteiligung beim Inverkehrbringen hat den Produkten jedoch vielfach den Ruf eingebracht, ungeprüft und deshalb nicht sicher zu sein. Bereits im Vorfeld der Veranstaltung in Berlin waren die Verbände dieser auch in Presse und Medien geäußerten Meinung in mehreren gemeinsamen Pressemitteilungen entschieden entgegengetreten. Dass das Interesse an der Thematik auch in der Politik groß ist, zeigte sich sodann beim parlamentarischen Mittagsempfang Ende April in der deutschen parlamentarischen Gesellschaft: Insgesamt 15 Bundestagsabgeordnete der Fraktionen CDU/CSU, SPD, FDP und die LINKE fanden sich zum gemeinsamen Diskurs ein. Den Auftakt zur Veranstaltung machte Herr Dr. Rolf Koschorrek (CDU), der ein Grußwort an die Gäste aus Politik, Verbänden und Industrie richtete. Er hob die „hohe Kultur“ der Medizinprodukte Deutschland hervor, betonte aber zugleich, dass man sich gegen kriminelle Energie, wie sie sich im Skandal um die Brustimplantate zeigte, auch mit dem besten System nicht schützen könne. Dennoch müsse alles getan werden, um zu verhindern, dass sich solche Vorfälle wiederholten. Die Qualität der Produkte müsse im Mittelpunkt stehen, da der Fokus jeglicher Bemühungen der Patient sei. Dabei gelte es andererseits eine Überbürokratisierung zu verhindern. Daran knüpften die weiteren Statements an. Stellvertretend für die Branchenverbände der Medizinprodukte-Industrie bekräftigten Joachim Schmitt (BVMed) und Hans-Peter Bursig (ZVEI), dass Patientenwohl und Patientenschutz nach wie vor die höchste Priorität haben. Auch die Hersteller seien durch den PIP-Skandal aufgeschreckt worden. Die geltenden Zulassungsvorschriften seien jedoch vollkommen ausreichend. Die Voraussetzungen für eine Zulassung seien risikoadjustiert - je nach Klasse des Medizinproduktes - und mit denen im Arzneimittelrecht durchaus vergleichbar, wie auch eine vergleichende Analyse des Bundesgesundheitsministeriums (BMG) gezeigt habe. Dennoch gebe es Verbesserungsbedarf: „Wir haben kein Regelungsdefizit, sondern ein Vollzugsdefizit“, so Schmitt. Die Branchenverbände der Medizinprodukte-Industrie hatten bereits zuvor Vorschläge und Forderungen zur Weiterentwicklung des bestehenden Systems vorgelegt, die beim Mittagsempfang erneut präsentiert und von den Teilnehmern diskutiert wurden. Im Gespräch tauschten sich Politiker und Industrievertreter darüber aus, wie die Meldevorschriften bei Vorkommnissen mit Medizinprodukten verbessert und die Marktüberwachung der Behörden zwischen den Mitgliedsstaaten intensiver koordiniert werden können. Auch die Wichtigkeit ein einheitliches Qualitätsniveau der Benannten Stellen europaweit sicherzustellen, wurde betont. Nicht zuletzt müsse auch die Möglichkeit zu unangemeldeten Kontrollen stärker genutzt und die Überwachungsbehörden personell und materiell besser ausgestattet werden, um - wo notwendig - die Sanktionsmöglichkeit bei Verstößen noch konsequenter nutzen zu können.

Der BAH hatte an einem Treffen im BMG teilgenommen, bei dem insbesondere die Klassifizierungskriterien nach Anhang VII (vgl. Regel 21) sowie die Regelungen/Anhänge zur klinischen Bewertung (Anh. XIII) und zu klinischen Prüfungen (Anh. XIV) diskutiert wurden. Die Geschäftsführung des BAH hatte hierzu ebenfalls ein Gespräch beim Ministerium. Wie mehrfach berichtet (RS Nr. 18 v. 10.06. und Nr. 20 v. 24.06.13) ist im Hinblick auf stoffliche Medizinprodukte insbesondere die Regel 21 als äußerst kritisch anzusehen, da eine Vielzahl sicherer Produkte hierdurch in Klasse III eingestuft würden. Dies wiederum führt nach den vorliegenden Vorschlägen zu einem immensen Mehraufwand bei der Marktzulassung, u.a. auch durch Verschärfungen bei der klinischen Bewertung (Einschränkung des Literaturwegs) und den gleichzeitig deutlich steigenden Anforderungen an klinische Prüfungen. Das BMG vertritt die deutsche Position im Ministerrat, wo sich zunächst die Mitgliedstaaten auf einen Standpunkt einigen müssen. Unter der neuen litauischen Ratspräsidentschaft bis Ende des Jahres sind hierzu vier Sitzungen der zuständigen Ratsarbeitsgruppe geplant, nachdem bereits unter der vorangegangenen irischen Präsidentschaft sieben Sitzungen stattgefunden hatten. Hinzu kommen Expertentreffen, die bislang noch nicht terminiert sind. Zuletzt hatte die zuständige Ratsarbeitsgruppe am 16.07.13 die Artikel 4-15 (Kap. II, Bereitstellung von Produkten, Pflichten der Wirtschaftsakteure …) sowie Artikel 56-60 (Informationsaustausch bezügl. klinischer Prüfungen) diskutiert. Verhandlungen des Ministerrates mit dem EU-Parlament werden wahrscheinlich erst nach der ersten Lesung im Parlament aufgenommen werden können, die Ende Oktober 2013 erwartet wird. Im zuständigen Ausschuss des Parlaments für Umweltfragen, öffentliche Gesundheit und Lebensmittelsicherheit (ENVI) des Europäischen Parlaments konnte bislang aufgrund der Vielzahl von Änderungsanträgen und kontroversen Vorschlägen (z.B. behördliche Zulassung bestimmter Medizinprodukte) keine Einigung erzielt werden. In Folge musste die Abstimmung über den Bericht von Frau Roth-Behrendt, die ursprünglich für den 10. Juli 2013 vorgesehen war, auf den 18. September 2013 verschoben worden. Das BMG bittet nun darum, anhand konkreter Produktbeispiele zu belegen, wie hoch die Kosten bzw. die Mehrbelastung wären, die durch die Vorschläge der Kommission bei den Herstellern entstehen würden. Dies betrifft vorerst die nun verhandelten Aspekte der (Höher-) Klassifizierung und klinischen Bewertung/Prüfung (vgl. oben). Die einzelnen gesetzlichen Anforderungen des Kommissionsvorschlags sollten dementsprechend von den Herstellern bewertet werden. Beispiele für Mehrbelastungen könnten beispielsweise sein: Steigerung der Personalkosten (Regulatory Affairs), Mehrkosten klinische Prüfungen (z.B. Outsourcing an CRO), Mehrkosten für Benannte Stellen, Verzögerung des Markteintritts (Investitionen). Hierbei sind speziell auch KMU angesprochen, die durch den steigenden Verwaltungsaufwand besonders betroffen wären. Auch begründete Schätzungen sind bei dieser komplexen Fragestellung bereits hilfreich und können unsere Position unterstützen. Der BAH bittet daher die betroffenen Mitgliedsunternehmen, entsprechende Daten bis spätestens Donnerstag, 08. August 2013, an den Verband zu übermitteln. Die Daten werden selbstverständlich vertraulich behandelt und nicht weitergegeben. Es wird lediglich eine anonymisierte Auswertung, die den einzelnen Absätzen des Verordnungsentwurfs zugeordnet ist, an das BMG übermittelt.

Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL) - Anlage I (OTC-Übersicht): Nummer 11 (Calciumverbindungen und Vitamin D) Vom 17. Januar 2013 Der Gemeinsame Bundesausschuss hat in seiner Sitzung am 17. Januar 2013 beschlossen, die Richtlinie über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung (Arzneimittel-Richtlinie) in der Fassung vom 18. Dezember 2008 / 22. Januar 2009 (BAnz. Nr. 49a vom 31. März 2009), zuletzt geändert am T. Monat JJJJ BAnz AT TT.MM.JJJJ V [Veröffentlichungsnummer manuell hinzufügen], wie folgt zu ändern: I. In Anlage I Nummer 11 werden nach den Wörtern „Calciumverbindungen (mind. 300 mg Calcium-Ion/Dosiereinheit) und Vitamin D (freie oder fixe Kombination)“ die Wörter „sowie Vitamin D als Monopräparat bei ausreichender Calciumzufuhr über die Nahrung“ eingefügt. II. Die Änderung der Arzneimittel-Richtlinie tritt am Tag nach der Veröffentlichung im Bundesanzeiger in Kraft. Die Tragenden Gründe zu diesem Beschluss werden auf der Internetseite des Gemeinsamen Bundesausschusses unter www.g-ba.de veröffentlicht. Berlin, den 17. Januar 2013 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hecken BAnz AT 04.04.2013 B3 http://www.g-ba.de/

Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL) - Anlage I (OTC-Übersicht): Nummer 11 (Calciumverbindungen und Vitamin D) Vom 17. Januar 2013 Inhalt 1. Rechtsgrundlage .......................................................................................................... 2 2. Eckpunkte der Entscheidung ...................................................................................... 2 3. Bürokratiekosten .......................................................................................................... 2 4. Verfahrensablauf .......................................................................................................... 3 5. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens ........................................................................................... 5 6. Unterlagen des Stellungnahmeverfahrens ................................................................. 7 6.1 Übersicht der eingegangenen Stellungnahmen ........................................................16 2 1. Rechtsgrundlage Nach § 34 Abs. 1 Satz 1 SGB V sind nicht verschreibungspflichtige Arzneimittel von der Versorgung nach § 31 SGB V ausgeschlossen. Der Gemeinsame Bundesausschuss legt gemäß § 34 Abs. 1 Satz 2 SGB V in den Richtlinien nach § 92 Abs. 1 Satz 2 Nr. 6 SGB V fest, welche nicht verschreibungspflichtigen Arzneimittel, die bei der Behandlung schwerwiegender Erkrankungen als Therapiestandard gelten, zur Anwendung bei diesen Erkrankungen mit Begründung vom Vertragsarzt ausnahmsweise verordnet werden können. Dabei ist der therapeutischen Vielfalt Rechnung zu tragen (§ 34 Abs. 1 Satz 3 SGB V). Gemäß § 34 Abs. 1 Satz 5 SGB V gilt der Ausschluss nach Satz 1 nicht für 1. versicherte Kinder bis zum vollendeten 12. Lebensjahr, 2. versicherte Jugendliche bis zum vollendeten 18. Lebensjahr mit Entwicklungsstörungen. Die gesetzlichen Kriterien sind in § 12 Abs. 3 und 4 der gültigen Arzneimittel-Richtlinie wie folgt konkretisiert: § 12 Abs. 3 Eine Krankheit ist schwerwiegend, wenn sie lebensbedrohlich ist oder wenn sie aufgrund der Schwere der durch sie verursachten Gesundheitsstörung die Lebensqualität auf Dauer nachhaltig beeinträchtigt. § 12 Abs. 4 Ein Arzneimittel gilt als Therapiestandard, wenn der therapeutische Nutzen zur Behandlung der schwerwiegenden Erkrankung dem allgemein anerkannten Stand der medizinischen Erkenntnisse entspricht. 2. Eckpunkte der Entscheidung Nach Anlage I Nummer 11 besteht bereits eine ausnahmsweise Verordnungsfähigkeit für Calciumverbindungen (mind. 300 mg Calcium-Ion/Dosiereinheit) und Vitamin D (in freier oder fixer Kombination) zur Behandlung der manifesten Osteoporose, zeitgleich zur Steroidtherapie bei Erkrankungen, die voraussichtlich einer mindestens sechsmonatigen Steroidtherapie in einer Dosis von wenigstens 7,5 mg Prednisolonäquivalent bedürfen und bei Bisphosphonat-Behandlung gemäß Angabe in der jeweiligen Fachinformation bei zwingender Notwendigkeit. Zur Klarstellung, dass Vitamin D bei ausreichender Calciumzufuhr über die Nahrung auch als Monopräparat zur Behandlung der aufgeführten Erkrankungen verordnungsfähig ist, wird die Formulierung von Nummer 11 konkretisiert. In Anlage I Nummer 11 werden deshalb nach den Wörtern „Calciumverbindungen (mind. 300 mg Calcium-Ion/Dosiereinheit) und Vitamin D (freie oder fixe Kombination)“ die Wörter „sowie Vitamin D als Monopräparat bei ausreichender Calciumzufuhr über die Nahrung“ eingefügt. 3. Bürokratiekosten Durch die im Beschluss enthaltenen Regelungen entstehen keine Informationspflichten für Leistungserbringerinnen und Leistungserbringer im Sinne von Anlage II zum 1. Kapitel VerfO. Daher entstehen auch keine Bürokratiekosten. 3 4. Verfahrensablauf Mit der Vorbereitung seiner Beschlüsse hat der Unterausschuss „Arzneimittel“ eine Arbeitsgruppe beauftragt, die sich aus den von den Spitzenorganisationen der Leistungserbringer benannten Mitgliedern, der vom GKV-Spitzenverband benannten Mitglieder sowie Vertreter(innen) der Patientenorganisationen zusammensetzt. In der Sitzung am 11. September 2012 hat der Unterausschuss „Arzneimittel“ die Einleitung des Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie, Anlage I (OTC- Übersicht) nach der Überprüfung der tatbestandlichen Voraussetzungen nach § 34 Abs. 1 Satz 2 in Verbindung mit § 12 Abs. 3 und 4 der Arzneimittel-Richtlinie sowie Kapitel 4 § 31 Abs. 1 und 2 Verfahrensordnung (VerfO) für die Nummer 11 abschließend beraten und nach § 10 Abs. 1, 1. Kapitel der Verfahrensordnung des G-BA die Einleitung eines Stellungnahmeverfahrens einstimmig beschlossen. In Anlage I Nummer 11 werden nach den Wörtern „Calciumverbindungen (mind. 300 mg Calcium-Ion/Dosiereinheit) und Vitamin D (freie oder fixe Kombination)“ die Wörter „sowie Vitamin D als Monopräparat bei ausreichender Calciumzufuhr über die Nahrung“ eingefügt. Es sind keine Stellungnahmen eingegangen. Demzufolge war eine mündliche Anhörung nach § 91 Abs. 9 S. 1 SGB V i. V. m. 1. Kapitel § 12 Abs. 1 VerfO des G-BA nicht durchzuführen. Insofern stellen die vorliegenden Tragenden Gründe den aktuellen Stand der zusammenfassenden Dokumentation dar. Der Unterausschuss „Arzneimittel“ hat in seiner Sitzung am 11. Dezember 2012 den Beschlussentwurf zur Änderung Anlage I ohne weitere Änderungen konsentiert. Das Plenum hat in seiner Sitzung am 17. Januar 2013 die Änderung der AM-RL in Anlage I beschlossen. Zeitlicher Beratungsverlauf Sitzung Datum Beratungsgegenstand AG „Nutzenbewertung“ 2. März 2012 Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC- Übersicht) AG „Nutzenbewertung“ 18. Juli 2012 Beratung zum Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) Nummer 11 Sitzung UA „Arzneimittel“ 11. September 2012 Beratung und Konsentierung des Beschlusses zur Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) Sitzung des Unterausschusses „Arzneimittel“ 11. Dezember 2012 Beratung und Konsentierung des Beschlussentwurfs zur Änderung der Anlage I der AM-RL Sitzung des Plenums 17. Januar .2013 Beschlussfassung über die Änderung der Anlage I der AM-RL 4 Berlin, den 17. Januar 2013 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hecken 5 5. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens Gemäß § 92 Abs. 3a SGB V ist den Sachverständigen der medizinischen und pharmazeutischen Wissenschaft und Praxis sowie den für die Wahrnehmung der wirtschaftlichen Interessen gebildeten maßgeblichen Spitzenorganisationen der pharmazeutischen Unternehmer, den betroffenen pharmazeutischen Unternehmern, den Berufsvertretungen der Apotheker und den maßgeblichen Dachverbänden der Ärztegesellschaften der besonderen Therapierichtungen auf Bundesebene Gelegenheit zur Stellungnahme zu geben. Folgende Organisationen wurden angeschrieben: Organisation Straße Ort Bundesverband der Pharmazeutischen Industrie e. V. (BPI) Friedrichstr. 148 10117 Berlin Verband Forschender Arzneimittelhersteller e. V. (VFA) Hausvogteiplatz 13 10117 Berlin Deutscher Zentralverein Homöopathischer Ärzte e.V. Reinhardtstraße 37 10117 Berlin Bundesverband der Arzneimittel-Importeure e.V. (BAI) EurimPark 8 83416 Saaldorf Bundesverband der Arzneimittel-Hersteller e.V. (BAH) Ubierstraße 73 53173 Bonn Deutscher Generikaverband e.V. Kurfürstendamm 190-102 10707 Berlin Gesellschaft für Phytotherapie e.V. Postfach 10 08 88 18055 Rostock Pro Generika e.V. Unter den Linden 32 - 34 10117 Berlin Gesellschaft Anthroposophischer Ärzte e.V. Roggenstraße 82 70794 Filderstadt Arzneimittelkommission der Deutschen Ärzteschaft (AkdÄ) Herbert-Lewin-Platz 1 10623 Berlin Bundesvereinigung Deutscher Apothekerverbände (ABDA) Deutsches Apothekerhaus Jägerstraße 49/50 10117 Berlin Arzneimittelkommission der Deutschen Zahnärzteschaft (AK-Z) c/o Bundeszahnärztekammer Chausseestr. 13 10115 Berlin Darüberhinaus wurde die Einleitung des Stellungnahmeverfahrens im Bundesanzeiger bekanntgemacht (BAnz AT 05.10.2012 B1). 6 7 6. Unterlagen des Stellungnahmeverfahrens 8 9 10 Stellungnahmeverfahren zum Thema „OTC – Änderung der Nummer 11“ Literaturliste [Hier Institution / Firma eingeben] Indikation [Hier zutreffende Indikation eingeben] Nr. Feldbezeichnung Text AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: AU: TI: SO: 11 12 13 14 15 16 6.1 Übersicht der eingegangenen Stellungnahmen Es sind keine Stellungnahmen eingegangen. 1. Rechtsgrundlage 2. Eckpunkte der Entscheidung 3. Bürokratiekosten 4. Verfahrensablauf 5. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens 6. Unterlagen des Stellungnahmeverfahrens 6.1 Übersicht der eingegangenen Stellungnahmen

Beschluss des Gemeinsamen Bundesausschusses über die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht: Nummer 2 (Acetylsalicylsäure) Vom 9. Oktober 2012 Der Unterausschuss „Arzneimittel“ hat in seiner Sitzung am 9. Oktober 2012 die Einleitung eines Stellungnahmeverfahrens zur Änderung der Richtlinie über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung (Arzneimittel-Richtlinie) in der Fassung vom 18. Dezember 2008 / 22. Januar 2009 (BAnz. Nr. 49a vom 31. März 2009), zuletzt geändert am T. Monat JJJJ (BAnz AT TT.MM.JJJJ B), beschlossen: I. In Anlage I Nummer 2 werden nach der Angabe „Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten- Aggregationshemmer“ die Wörter „bei koronarer Herzkrankheit (gesichert durch Symptomatik und ergänzende nicht-invasive oder invasive Diagnostik) und“ eingefügt. II. Die Änderung der Arzneimittel-Richtlinie tritt am Tage nach der Veröffentlichung im Bundesanzeiger in Kraft. Die Tragenden Gründe zu diesem Beschluss werden auf der Internetseite des Gemeinsamen Bundesausschusses unter www.g-ba.de veröffentlicht. Berlin, den 9. Oktober 2012 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hecken http://www.g-ba.de/ des Gemeinsamen Bundesausschussesüber die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht: Nummer 2 (Acetylsalicylsäure) Vom 9. Oktober 2012 Der Unterausschuss „Arzneimittel“ hat in seiner Sitzung am 9. Oktober 2012 die Einleitung eines Stellungnahmeverfahrens zur Änderung der Richtlinie über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung (Arzneimittel-Richtlinie) in der Fassung vom 18. Dezember 2008 / 22. Januar 2009 (BAnz. Nr. 49a vom 31. März 2009), zuletzt geändert am T. Monat JJJJ (BAnz AT TT.MM.JJJJ B), beschlossen: I. In Anlage I Nummer 2 werden nach der Angabe „Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten- Aggregationshemmer“ die Wörter „bei koronarer Herzkrankheit (gesichert durch Symptomatik und ergänzende nicht-invasive oder invasive Diagnostik) und“ eingefügt. II. Die Änderung der Arzneimittel-Richtlinie tritt am Tage nach der Veröffentlichung im Bundesanzeiger in Kraft. Die Tragenden Gründe zu diesem Beschluss werden auf der Internetseite des Gemeinsamen Bundesausschusses unter www.g-ba.de veröffentlicht. Berlin, den 9. Oktober 2012 Gemeinsamer Bundesausschussgemäß § 91 SGB VDer Vorsitzende Hecken

Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht: Nummer 2 (Acetylsalicylsäure) Vom 9. Oktober 2012 Inhalt 1. Rechtsgrundlage .......................................................................................................... 2 2. Eckpunkte der Entscheidung ...................................................................................... 2 3. Verfahrensablauf .......................................................................................................... 4 2 1. Rechtsgrundlage Nach § 34 Abs. 1 Satz 1 SGB V sind nicht verschreibungspflichtige Arzneimittel von der Versorgung nach § 31 SGB V ausgeschlossen. Der Gemeinsame Bundesausschuss legt gemäß § 34 Abs. 1 Satz 2 SGB V in den Richtlinien nach § 92 Abs. 1 Satz 2 Nr. 6 SGB V fest, welche nicht verschreibungspflichtigen Arzneimittel, die bei der Behandlung schwerwiegender Erkrankungen als Therapiestandard gelten, zur Anwendung bei diesen Erkrankungen mit Begründung vom Vertragsarzt ausnahmsweise verordnet werden können. Dabei ist der therapeutischen Vielfalt Rechnung zu tragen (§ 34 Abs. 1 Satz 3 SGB V). Gemäß § 34 Abs. 1 Satz 5 SGB V gilt der Ausschluss nach Satz 1 nicht für 1. versicherte Kinder bis zum vollendeten 12. Lebensjahr, 2. versicherte Jugendliche bis zum vollendeten 18. Lebensjahr mit Entwicklungsstörungen. Die gesetzlichen Kriterien sind in § 12 Abs. 3 und 4 der gültigen Arzneimittel-Richtlinie wie folgt konkretisiert: § 12 Abs. 3 Eine Krankheit ist schwerwiegend, wenn sie lebensbedrohlich ist oder wenn sie aufgrund der Schwere der durch sie verursachten Gesundheitsstörung die Lebensqualität auf Dauer nachhaltig beeinträchtigt. § 12 Abs. 4 Ein Arzneimittel gilt als Therapiestandard, wenn der therapeutische Nutzen zur Behandlung der schwerwiegenden Erkrankung dem allgemein anerkannten Stand der medizinischen Erkenntnisse entspricht. 2. Eckpunkte der Entscheidung Der G-BA hat im Rahmen seiner regelmäßigen Überprüfung die Notwendigkeit einer Überarbeitung der Anlage I Nr. 2 (Acetylsalicylsäure) festgestellt. In Anlage I (so genannte OTC-Übersicht) besteht in Nummer 2 bereits eine ausnahmsweise Verordnungsfähigkeit für Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten- Aggregationshemmer in der Nachsorge von Herzinfarkt und Schlaganfall sowie nach arteriellen Eingriffen. Die Verwendung von Acetylsalicylsäure (bis 300 mg/Dosiseinheit) entspricht auch in der Sekundärprävention bei der Behandlung der koronaren Herzkrankheit (KHK) dem allgemein anerkannten Stand der medizinischen Erkenntnisse und gilt dabei als Therapiestandard. Unter dem Begriff akutes Koronarsyndrom werden die Phasen der koronaren Herzerkrankung zusammengefasst, die unmittelbar lebensbedrohlich sind, hierzu gehören die instabile Angina pectoris, der akute Myokardinfarkt und der plötzliche Herztod. Eine KHK ist mit einem erhöhten Morbiditäts- und Mortalitätsrisiko verbunden. Sie geht häufig mit der Symptomatik der Angina pectoris einher. Die Lebensqualität kann sowohl dadurch als auch über die aus der KHK resultierende Leistungseinschränkung reduziert sein. Bei älteren Patienten, speziell Frauen oder Diabetikern, kann die myokardiale Ischämie auch ohne Angina pectoris auftreten. Die KHK stellt damit eine schwerwiegende Erkrankung im Sinne der Arzneimittelrichtlinie § 12 Abs. 3 dar. Die Diagnose einer koronaren Herzkrankheit kann mit hinreichend hoher Wahrscheinlichkeit gestellt werden, wenn sich aus Symptomatik, klinischer Untersuchung, Anamnese, Begleiterkrankungen und Belastungs-EKG eine hohe Wahrscheinlichkeit (mindestens 90 %) für das Vorliegen einer koronaren Herzkrankheit belegen lässt. Nur bei Patienten, die nach Feststellung der Ärztin oder des Arztes aus gesundheitlichen Gründen für ein Belastungs- 3 EKG nicht in Frage kommen oder bei denen ein auswertbares Ergebnis des Belastungs- EKGs nicht erreichbar ist (insbesondere bei Patienten mit Linksschenkelblock, Herzschrittmacher oder bei Patienten, die physikalisch nicht belastbar sind), können andere nicht-invasive Untersuchungen zur Diagnosesicherung (echokardiografische oder szintigrafische Verfahren) angewendet werden. Auch wenn ein akutes Koronarsyndrom aufgetreten ist oder wenn die KHK direkt mittels Koronarangiografie nachgewiesen wurde gilt die Diagnose als gesichert. In Anlage I Nummer 2 werden daher nach der Angabe „Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten- Aggregationshemmer“ die Wörter „bei koronarer Herzkrankheit (gesichert durch Symptomatik und ergänzende nicht-invasive oder invasive Diagnostik) und“ eingefügt. Die Thrombozyten-Aggregationshemmung mit Acetylsalicylsäure gilt als ein Therapiestandard in der Behandlung der KHK, wobei Dosierungen auch unterhalb 300 mg/Dosiseinheit zur Erreichung vergleichbarer Effekte bei besserer Verträglichkeit diskutiert werden. In einer Meta-Analyse wurden sechs randomisierte kontrollierte Studien mit insgesamt 6.300 Patienten bewertet, die Acetylsalicylsäure (50 bis 325 mg) oder Placebo in der Sekundärprävention erhielten. Die Patienten hatten einen Schlaganfall, Myokardinfarkt oder eine stabile Angina pectoris in der Vorgeschichte. Die Einnahme von Acetylsalicylsäure reduzierte das Mortalitätsrisiko um 18 % (RR 0,82; 95 % KI (0,7-0,9) p = 0,03). Es zeigte sich zudem eine relative Risikoreduktion für Myokardinfarkt und vaskuläre Ereignisse (zusammengesetzt aus Myokardinfarkt, Schlaganfall und andere vaskuläre Ereignisse) um jeweils 30 % (RR 0,7; 95 % KI (0,6-0,8); p = <0,001). Die Einnahme von Acetylsalicylsäure war mit einer Erhöhung des Risikos für gastrointestinale Blutungen verbunden, allerdings wurden in den sechs Studien nur 58 Fälle berichtet (41 in der Acetylsalicylsäure-Gruppe und 17 in der Placebo-Gruppe (RR 2,5; 95 % KI (1,4-4,7)). Es wurden keine Todesfälle identifiziert, die auf Blutungen zurückzuführen waren1. In einer weiteren Meta-Analyse (Antithrombotic Trialists´ Collaboration) wurden 195 randomisierte, kontrollierte Studien mit 135.640 Patienten mit hohem Risiko bewertet, bei denen Endpunkte zu vaskulären Ereignissen vorlagen. Die Patienten erhielten entweder eine Thrombozytenaggregationshemmung oder Placebo (Kontrolle). Acetylsalicylsäure war der am häufigsten untersuchte Thrombozytenaggregationshemmer2. Sieben dieser Studien untersuchten Patienten (insgesamt 2920) mit stabiler Angina pectoris. Unter der Gabe eines Thrombozytenaggregationshemmers hatten 144 von 1448 Patienten mit stabiler Angina pectoris ein vaskuläres Ereignis, während dies in der Kontrollgruppe bei 208 von 1472 Patienten der Fall war. Ein vaskuläres Ereignis war definiert als nicht-tödlicher Herzinfarkt, nicht-tödlicher Schlaganfall oder Tod aufgrund eines vaskulären Ereignisses. Die Wahrscheinlichkeit für ein vaskuläres Ereignis war bei Patienten mit stabiler Angina pectoris unter der Gabe eines Thrombozytenaggregationshemmers um 33 % (SE = 9; p = 0,0005) reduziert. Die Autoren kommen zu dem Schluss, dass eine Thrombozytenaggregations- hemmung Patienten mit stabiler Angina pectoris vor vaskulären Ereignissen schützt2. Hier ist ergänzend auf die in die Meta-Analyse eingeflossene Studie von Juul-Möller et al. (1992) hinzuweisen, in der eine Überlegenheit von Acetylsalicylsäure gegenüber Placebo jeweils in 1 Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002; 162: 2197-202 2 Antithrombotic Trialists´ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86 4 Komedikation mit Sotalol bei Patienten mit stabiler Angina pectoris in Hinblick auf die primären Endpunkte Myokardinfarkt und plötzlicher Tod gezeigt wurde3. Die Meta-Analyse der Antithrombotic Trialists´ Collaboration schloss auch 12 Studien mit Patienten mit instabiler Angina pectoris (insgesamt 5031 Patienten) ein. In der Gruppe, die eine Thrombozytenaggregationshemmung erhielten, hatten 199 von 2497 Patienten mit instabiler Angina pectoris ein vaskuläres Ereignis, in der Kontrollgruppe erlitten 336 von 2534 Patienten ein vaskuläres Ereignis. Die Wahrscheinlichkeit für ein vaskuläres Ereignis war bei Patienten mit instabiler Angina pectoris unter der Gabe eines Thrombozytenaggregationshemmers um 46 % (SE = 7; p < 0,0001) reduziert2. Die Meta-Analyse untersuchte auch die Effekte verschiedener Dosierungen von Acetylsalicylsäure. Dabei zeigte sich bei Dosen von 500-1500 mg pro Tag eine Reduktion vaskulärer Ereignisse von 19 % (SE = 3 %), bei 160-325 mg pro Tag von 26 % (SE = 3 %) und bei 75-150 mg pro Tag von 32 % (SE = 6 %). Dosen < 75 mg pro Tag hatten einen geringeren Effekt. Er betrug 13 % (SE = 8 %)2. 3. Verfahrensablauf Mit der Vorbereitung seiner Beschlüsse hat der Unterausschuss „Arzneimittel“ eine Arbeitsgruppe beauftragt, die sich aus den von den Spitzenorganisationen der Leistungserbringer benannten Mitgliedern, der vom GKV-Spitzenverband benannten Mitglieder sowie Vertreter(innen) der Patientenorganisationen zusammensetzt. In der Sitzung am 9. Oktober 2012 hat der Unterausschuss „Arzneimittel“ die Einleitung des Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie, Anlage I (OTC- Übersicht) nach der Überprüfung der tatbestandlichen Voraussetzungen nach § 34 Abs. 1 Satz 2 in Verbindung mit § 12 Abs. 3 und 4 der Arzneimittel-Richtlinie sowie Kapitel 4 § 31 Abs. 1 und 2 Verfahrensordnung (VerfO) für die Nummer 2 abschließend beraten und nach § 10 Abs. 1, 1. Kapitel der Verfahrensordnung des G-BA die Einleitung eines Stellungnahmeverfahrens einstimmig beschlossen. Zeitlicher Beratungsverlauf Sitzung Datum Beratungsgegenstand AG „Nutzenbewertung“ 28. November 2011 Beratung zur Änderung der Arzneimittel- Richtlinie in Anlage I (OTC-Übersicht) Nr. 2 AG „Nutzenbewertung“ 2. März 2012 Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC- Übersicht) AG „Nutzenbewertung“ 18. Juli 2012 Beratung zum Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) Sitzung UA „Arzneimittel“ 9. Oktober 2012 Beratung und Konsentierung des Beschlusses zur Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) 3 Juul-Möller S et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group. Lancet 1992; 340: 1421-5 5 Zum Zeitpunkt der Einleitung des Stellungnahmeverfahrens stellen die vorliegenden Tragenden Gründe den aktuellen Stand der zusammenfassenden Dokumentation dar, welche den stellungnahmeberechtigten Organisationen zur Verfügung zu stellen sind (1. Kapitel § 10 Abs. 2, VerfO G-BA). Gemäß § 92 Abs. 3a SGB V wird den Sachverständigen der medizinischen und pharmazeutischen Wissenschaft und Praxis sowie den für die Wahrnehmung der wirtschaftlichen Interessen gebildeten maßgeblichen Spitzenorganisationen der pharmazeutischen Unternehmer, den betroffenen pharmazeutischen Unternehmern, den Berufsvertretungen der Apotheker und den maßgeblichen Dachverbänden der Ärztegesellschaften der besonderen Therapierichtungen auf Bundesebene Gelegenheit zur Stellungnahme gegeben. Eine Stellungnahme zur Richtlinienänderung ist durch Literatur (z. B. relevante Studien) zu begründen. Die zitierte Literatur ist obligat im Volltext inklusive einem standardisierten und vollständigen Literatur- bzw. Anlagenverzeichnis der Stellungnahme beizufügen. Nur Literatur, die im Volltext beigefügt ist, kann berücksichtigt werden. Mit Abgabe einer Stellungnahme erklärt sich der Stellungnehmer einverstanden, dass diese in den Tragenden Gründen bzw. in der zusammenfassenden Dokumentation wiedergegeben werden kann. Diese Dokumente werden jeweils mit Abschluss der Beratungen im Gemeinsamen Bundesausschuss erstellt und in der Regel der Öffentlichkeit via Internet zugänglich gemacht. 6 Folgende Organisationen werden angeschrieben: Organisation Straße Ort Bundesverband der Pharmazeutischen Industrie e. V. (BPI) Friedrichstr. 148 10117 Berlin Verband Forschender Arzneimittelhersteller e. V. (VFA) Hausvogteiplatz 13 10117 Berlin Deutscher Zentralverein Homöopathischer Ärzte e.V. Reinhardtstraße 37 10117 Berlin Bundesverband der Arzneimittel-Importeure e.V. (BAI) EurimPark 8 83416 Saaldorf Bundesverband der Arzneimittel-Hersteller e.V. (BAH) Ubierstraße 73 53173 Bonn Deutscher Generikaverband e.V. Kurfürstendamm 190-102 10707 Berlin Gesellschaft für Phytotherapie e.V. Postfach 10 08 88 18055 Rostock Pro Generika e.V. Unter den Linden 32 - 34 10117 Berlin Gesellschaft Anthroposophischer Ärzte e.V. Roggenstraße 82 70794 Filderstadt Arzneimittelkommission der Deutschen Ärzteschaft (AkdÄ) Herbert-Lewin-Platz 1 10623 Berlin Bundesvereinigung Deutscher Apothekerverbände (ABDA) Deutsches Apothekerhaus Jägerstraße 49/50 10117 Berlin Arzneimittelkommission der Deutschen Zahnärzteschaft (AK-Z) c/o Bundeszahnärztekammer Chausseestr. 13 10115 Berlin Die Einleitung des Stellungnahmeverfahrens wird im Bundesanzeiger bekanntgemacht. Als Frist zur Stellungnahme wird ein Zeitraum von 4 Wochen vorgesehen. Berlin, den 9. Oktober 2012 Gemeinsamer Bundesausschuss gemäß § 91 SGB V Der Vorsitzende Hecken zum Beschluss des Gemeinsamen Bundesausschussesüber die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage I - OTC-Übersicht:Nummer 2 (Acetylsalicylsäure) Vom 9. Oktober 2012 Inhalt 1. Rechtsgrundlage 2 2. Eckpunkte der Entscheidung 2 3. Verfahrensablauf 4 1. Rechtsgrundlage Nach § 34 Abs. 1 Satz 1 SGB V sind nicht verschreibungspflichtige Arzneimittel von der Versorgung nach § 31 SGB V ausgeschlossen. Der Gemeinsame Bundesausschuss legt gemäß § 34 Abs. 1 Satz 2 SGB V in den Richtlinien nach § 92 Abs. 1 Satz 2 Nr. 6 SGB V fest, welche nicht verschreibungspflichtigen Arzneimittel, die bei der Behandlung schwerwiegender Erkrankungen als Therapiestandard gelten, zur Anwendung bei diesen Erkrankungen mit Begründung vom Vertragsarzt ausnahmsweise verordnet werden können. Dabei ist der therapeutischen Vielfalt Rechnung zu tragen (§ 34 Abs. 1 Satz 3 SGB V). Gemäß § 34 Abs. 1 Satz 5 SGB V gilt der Ausschluss nach Satz 1 nicht für 1. versicherte Kinder bis zum vollendeten 12. Lebensjahr, 2. versicherte Jugendliche bis zum vollendeten 18. Lebensjahr mit Entwicklungsstörungen. Die gesetzlichen Kriterien sind in § 12 Abs. 3 und 4 der gültigen Arzneimittel-Richtlinie wie folgt konkretisiert: § 12 Abs. 3 Eine Krankheit ist schwerwiegend, wenn sie lebensbedrohlich ist oder wenn sie aufgrund der Schwere der durch sie verursachten Gesundheitsstörung die Lebensqualität auf Dauer nachhaltig beeinträchtigt. § 12 Abs. 4 Ein Arzneimittel gilt als Therapiestandard, wenn der therapeutische Nutzen zur Behandlung der schwerwiegenden Erkrankung dem allgemein anerkannten Stand der medizinischen Erkenntnisse entspricht. 2. Eckpunkte der Entscheidung Der G-BA hat im Rahmen seiner regelmäßigen Überprüfung die Notwendigkeit einer Überarbeitung der Anlage I Nr. 2 (Acetylsalicylsäure) festgestellt. In Anlage I (so genannte OTC-Übersicht) besteht in Nummer 2 bereits eine ausnahmsweise Verordnungsfähigkeit für Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten-Aggregationshemmer in der Nachsorge von Herzinfarkt und Schlaganfall sowie nach arteriellen Eingriffen. Die Verwendung von Acetylsalicylsäure (bis 300 mg/Dosiseinheit) entspricht auch in der Sekundärprävention bei der Behandlung der koronaren Herzkrankheit (KHK) dem allgemein anerkannten Stand der medizinischen Erkenntnisse und gilt dabei als Therapiestandard. Unter dem Begriff akutes Koronarsyndrom werden die Phasen der koronaren Herzerkrankung zusammengefasst, die unmittelbar lebensbedrohlich sind, hierzu gehören die instabile Angina pectoris, der akute Myokardinfarkt und der plötzliche Herztod. Eine KHK ist mit einem erhöhten Morbiditäts- und Mortalitätsrisiko verbunden. Sie geht häufig mit der Symptomatik der Angina pectoris einher. Die Lebensqualität kann sowohl dadurch als auch über die aus der KHK resultierende Leistungseinschränkung reduziert sein. Bei älteren Patienten, speziell Frauen oder Diabetikern, kann die myokardiale Ischämie auch ohne Angina pectoris auftreten. Die KHK stellt damit eine schwerwiegende Erkrankung im Sinne der Arzneimittelrichtlinie § 12 Abs. 3 dar. Die Diagnose einer koronaren Herzkrankheit kann mit hinreichend hoher Wahrscheinlichkeit gestellt werden, wenn sich aus Symptomatik, klinischer Untersuchung, Anamnese, Begleiterkrankungen und Belastungs-EKG eine hohe Wahrscheinlichkeit (mindestens 90 %) für das Vorliegen einer koronaren Herzkrankheit belegen lässt. Nur bei Patienten, die nach Feststellung der Ärztin oder des Arztes aus gesundheitlichen Gründen für ein Belastungs-EKG nicht in Frage kommen oder bei denen ein auswertbares Ergebnis des Belastungs-EKGs nicht erreichbar ist (insbesondere bei Patienten mit Linksschenkelblock, Herzschrittmacher oder bei Patienten, die physikalisch nicht belastbar sind), können andere nicht-invasive Untersuchungen zur Diagnosesicherung (echokardiografische oder szintigrafische Verfahren) angewendet werden. Auch wenn ein akutes Koronarsyndrom aufgetreten ist oder wenn die KHK direkt mittels Koronarangiografie nachgewiesen wurde gilt die Diagnose als gesichert. In Anlage I Nummer 2 werden daher nach der Angabe „Acetylsalicylsäure (bis 300 mg/Dosiseinheit) als Thrombozyten- Aggregationshemmer“ die Wörter „bei koronarer Herzkrankheit (gesichert durch Symptomatik und ergänzende nicht-invasive oder invasive Diagnostik) und“ eingefügt. Die Thrombozyten-Aggregationshemmung mit Acetylsalicylsäure gilt als ein Therapiestandard in der Behandlung der KHK, wobei Dosierungen auch unterhalb 300 mg/Dosiseinheit zur Erreichung vergleichbarer Effekte bei besserer Verträglichkeit diskutiert werden. In einer Meta-Analyse wurden sechs randomisierte kontrollierte Studien mit insgesamt 6.300 Patienten bewertet, die Acetylsalicylsäure (50 bis 325 mg) oder Placebo in der Sekundärprävention erhielten. Die Patienten hatten einen Schlaganfall, Myokardinfarkt oder eine stabile Angina pectoris in der Vorgeschichte. Die Einnahme von Acetylsalicylsäure reduzierte das Mortalitätsrisiko um 18 % (RR 0,82; 95 % KI (0,7-0,9) p = 0,03). Es zeigte sich zudem eine relative Risikoreduktion für Myokardinfarkt und vaskuläre Ereignisse (zusammengesetzt aus Myokardinfarkt, Schlaganfall und andere vaskuläre Ereignisse) um jeweils 30 % (RR 0,7; 95 % KI (0,6-0,8); p = <0,001). Die Einnahme von Acetylsalicylsäure war mit einer Erhöhung des Risikos für gastrointestinale Blutungen verbunden, allerdings wurden in den sechs Studien nur 58 Fälle berichtet (41 in der Acetylsalicylsäure-Gruppe und 17 in der Placebo-Gruppe (RR 2,5; 95 % KI (1,4-4,7)). Es wurden keine Todesfälle identifiziert, die auf Blutungen zurückzuführen waren. In einer weiteren Meta-Analyse (Antithrombotic Trialists´ Collaboration) wurden 195 randomisierte, kontrollierte Studien mit 135.640 Patienten mit hohem Risiko bewertet, bei denen Endpunkte zu vaskulären Ereignissen vorlagen. Die Patienten erhielten entweder eine Thrombozytenaggregationshemmung oder Placebo (Kontrolle). Acetylsalicylsäure war der am häufigsten untersuchte Thrombozytenaggregationshemmer. Sieben dieser Studien untersuchten Patienten (insgesamt 2920) mit stabiler Angina pectoris. Unter der Gabe eines Thrombozytenaggregationshemmers hatten 144 von 1448 Patienten mit stabiler Angina pectoris ein vaskuläres Ereignis, während dies in der Kontrollgruppe bei 208 von 1472 Patienten der Fall war. Ein vaskuläres Ereignis war definiert als nicht-tödlicher Herzinfarkt, nicht-tödlicher Schlaganfall oder Tod aufgrund eines vaskulären Ereignisses. Die Wahrscheinlichkeit für ein vaskuläres Ereignis war bei Patienten mit stabiler Angina pectoris unter der Gabe eines Thrombozytenaggregationshemmers um 33 % (SE = 9; p = 0,0005) reduziert. Die Autoren kommen zu dem Schluss, dass eine Thrombozytenaggregations-hemmung Patienten mit stabiler Angina pectoris vor vaskulären Ereignissen schützt4. Hier ist ergänzend auf die in die Meta-Analyse eingeflossene Studie von Juul-Möller et al. (1992) hinzuweisen, in der eine Überlegenheit von Acetylsalicylsäure gegenüber Placebo jeweils in Komedikation mit Sotalol bei Patienten mit stabiler Angina pectoris in Hinblick auf die primären Endpunkte Myokardinfarkt und plötzlicher Tod gezeigt wurde. Die Meta-Analyse der Antithrombotic Trialists´ Collaboration schloss auch 12 Studien mit Patienten mit instabiler Angina pectoris (insgesamt 5031 Patienten) ein. In der Gruppe, die eine Thrombozytenaggregationshemmung erhielten, hatten 199 von 2497 Patienten mit instabiler Angina pectoris ein vaskuläres Ereignis, in der Kontrollgruppe erlitten 336 von 2534 Patienten ein vaskuläres Ereignis. Die Wahrscheinlichkeit für ein vaskuläres Ereignis war bei Patienten mit instabiler Angina pectoris unter der Gabe eines Thrombozytenaggregationshemmers um 46 % (SE = 7; p < 0,0001) reduziert2. Die Meta-Analyse untersuchte auch die Effekte verschiedener Dosierungen von Acetylsalicylsäure. Dabei zeigte sich bei Dosen von 500-1500 mg pro Tag eine Reduktion vaskulärer Ereignisse von 19 % (SE = 3 %), bei 160-325 mg pro Tag von 26 % (SE = 3 %) und bei 75-150 mg pro Tag von 32 % (SE = 6 %). Dosen < 75 mg pro Tag hatten einen geringeren Effekt. Er betrug 13 % (SE = 8 %)2. 3. Verfahrensablauf Mit der Vorbereitung seiner Beschlüsse hat der Unterausschuss „Arzneimittel“ eine Arbeitsgruppe beauftragt, die sich aus den von den Spitzenorganisationen der Leistungserbringer benannten Mitgliedern, der vom GKV-Spitzenverband benannten Mitglieder sowie Vertreter(innen) der Patientenorganisationen zusammensetzt. In der Sitzung am 9. Oktober 2012 hat der Unterausschuss „Arzneimittel“ die Einleitung des Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie, Anlage I (OTC-Übersicht) nach der Überprüfung der tatbestandlichen Voraussetzungen nach § 34 Abs. 1 Satz 2 in Verbindung mit § 12 Abs. 3 und 4 der Arzneimittel-Richtlinie sowie Kapitel 4 § 31 Abs. 1 und 2 Verfahrensordnung (VerfO) für die Nummer 2 abschließend beraten und nach § 10 Abs. 1, 1. Kapitel der Verfahrensordnung des G-BA die Einleitung eines Stellungnahmeverfahrens einstimmig beschlossen. Zeitlicher Beratungsverlauf Beratungsgegenstand Datum Sitzung Beratung zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) Nr. 2 28. November 2011 AG „Nutzenbewertung“ Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) 2. März 2012 AG „Nutzenbewertung“ Beratung zum Vorschlag der KBV zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) 18. Juli 2012 AG „Nutzenbewertung“ Beratung und Konsentierung des Beschlusses zur Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie in Anlage I (OTC-Übersicht) 9. Oktober 2012 Sitzung UA „Arzneimittel“ Zum Zeitpunkt der Einleitung des Stellungnahmeverfahrens stellen die vorliegenden Tragenden Gründe den aktuellen Stand der zusammenfassenden Dokumentation dar, welche den stellungnahmeberechtigten Organisationen zur Verfügung zu stellen sind (1. Kapitel § 10 Abs. 2, VerfO G-BA). Gemäß § 92 Abs. 3a SGB V wird den Sachverständigen der medizinischen und pharmazeutischen Wissenschaft und Praxis sowie den für die Wahrnehmung der wirtschaftlichen Interessen gebildeten maßgeblichen Spitzenorganisationen der pharmazeutischen Unternehmer, den betroffenen pharmazeutischen Unternehmern, den Berufsvertretungen der Apotheker und den maßgeblichen Dachverbänden der Ärztegesellschaften der besonderen Therapierichtungen auf Bundesebene Gelegenheit zur Stellungnahme gegeben. Eine Stellungnahme zur Richtlinienänderung ist durch Literatur (z. B. relevante Studien) zu begründen. Die zitierte Literatur ist obligat im Volltext inklusive einem standardisierten und vollständigen Literatur- bzw. Anlagenverzeichnis der Stellungnahme beizufügen. Nur Literatur, die im Volltext beigefügt ist, kann berücksichtigt werden. Mit Abgabe einer Stellungnahme erklärt sich der Stellungnehmer einverstanden, dass diese in den Tragenden Gründen bzw. in der zusammenfassenden Dokumentation wiedergegeben werden kann. Diese Dokumente werden jeweils mit Abschluss der Beratungen im Gemeinsamen Bundesausschuss erstellt und in der Regel der Öffentlichkeit via Internet zugänglich gemacht. Folgende Organisationen werden angeschrieben: Ort Straße Organisation 10117 Berlin Friedrichstr. 148 Bundesverband derPharmazeutischen Industrie e. V. (BPI) 10117 Berlin Hausvogteiplatz 13 Verband ForschenderArzneimittelhersteller e. V. (VFA) 10117 Berlin Reinhardtstraße 37 Deutscher ZentralvereinHomöopathischer Ärzte e.V. 83416 Saaldorf EurimPark 8 Bundesverband derArzneimittel-Importeure e.V. (BAI) 53173 Bonn Ubierstraße 73 Bundesverband der Arzneimittel-Hersteller e.V. (BAH) 10707 Berlin Kurfürstendamm 190-102 Deutscher Generikaverband e.V. 18055 Rostock Postfach 10 08 88 Gesellschaft für Phytotherapie e.V. 10117 Berlin Unter den Linden 32 - 34 Pro Generika e.V. 70794 Filderstadt Roggenstraße 82 Gesellschaft Anthroposophischer Ärzte e.V. 10623 Berlin Herbert-Lewin-Platz 1 Arzneimittelkommission der Deutschen Ärzteschaft (AkdÄ) 10117 Berlin Deutsches ApothekerhausJägerstraße 49/50 Bundesvereinigung Deutscher Apothekerverbände (ABDA) 10115 Berlin Chausseestr. 13 Arzneimittelkommission der Deutschen Zahnärzteschaft (AK-Z)c/o Bundeszahnärztekammer Die Einleitung des Stellungnahmeverfahrens wird im Bundesanzeiger bekanntgemacht. Als Frist zur Stellungnahme wird ein Zeitraum von 4 Wochen vorgesehen. Berlin, den 9. Oktober 2012 Gemeinsamer Bundesausschussgemäß § 91 SGB VDer Vorsitzende Hecken

Anlage 1 zu AW PV002 PAGE critical Final major External Audit of Pharmacovigilance Procedures Questionnaire for External Audit of Pharmacovigilance Procedures # Category Question Yes Doc No (Title) No N/A 1 General Does your company (your PV unit) perform a risk analysis? Do you have a written description (which can also be an organisation chart) of the organisation (which may only include one person) that is used to provide the local PV Unit function/capability/reporting? Do you have job descriptions and CVs for all positions/individuals primarily or directly involved in the ADRs collection, evaluation, processing and reporting functions? CVs: If kept outside Local PV Unit, can they be easily accessed? 2 QPPV For companies that are Marketing Authorisation Holders (MAHs), do you have a formal job description and CV specific for your Qualified Person for Pharmacovigilance (QPPV) position? Do you ensure that the QPPV has got an appropriate qualification, with documented experience in all aspects of PV? Is the QPPV medically qualified, or does he/she have access to medically qualified persons? Do you ensure that the QPPV will be available 24-hours as a contact point for national and international competent authorities? Are there valid back-up procedures in place to ensure business continuity and continued fulfilment of PV obligations? Are the name and 24-hour contact details of the QPPV and back-up procedures notified to the competent authorities? Do you ensure that the QPPV has adequate access to all relevant Pharmacovigilance/drug safety information? Do you ensure that the delegation of tasks by the QPPV is documented? 3 PSMF Do you have written document(s) that describe how the Pharmacovigilance System Master File (PSMF) is generated and updated? Is it specified who is responsible for notifying it to the competent authorities? Do you have a PSMF? Is the PSMF available? 4 Training QPPV and national competent person Do you have written document(s) that describe how the QPPV (including the national competent person) is adequately trained? Is this training adequately documented? 5 Training PV Unit personnel Do you have written document(s) that describe how PV Unit personnel are trained on local regulatory reporting timeframes, and receive periodic refresher training? Do you have a prospective training system for the PV Unit personnel? Do you assess the success of training? Do you have written document(s) that describe how the PV staff is adequately trained in all relevant PV aspects, including the proper use of the PV database and the current version of MedDRA? 6 Training logs Is it specified who is responsible for the generation and retention of training records for local PV Unit individuals primarily or directly involved in adverse event collection, processing, evaluation and reporting functions? Do you have written document(s) that describe these tasks? 7 Training of company departments Is your local Qualified Person for Pharmacovigilance and/or local PV Unit involved in training other departments in the company regarding adverse event collection? Do you have written document(s) that describe how the staff from other departments involved in any PV activities is adequately trained in all relevant PV aspects? Do you have a prospective training system, periodicity? Do you assess the success of the training? Filing of training documents? 8 Temporary personnel Is temporary personnel used for any of the functions involved in collecting, evaluating, processing or reporting of possible ADR? If yes, are steps taken to ensure that the temporary employees are adequately trained and have the appropriate education / experience? Are these steps described in written document(s)? 9 Role of the local PV Unit concerning contracts and legal agreements Do you have written document(s) to describe local PV Unit’s role with respect to contracts and other legal agreements that involve any aspects of safety? Do these materials specify:· - How contracts/legal agreements are kept current? - How compliance of partnering entity (e.g. company; CRO) is monitored? - How consistency between contracts/legal agreements is achieved? - Relationship between local PV Unit and Legal Department? - The role of the global PV Unit in review of contracts/legal agreements before they are signed? Does local PV Unit review all contracts and other legal agreements with respect to safety before they are finalized? Is there an original or copy of each signed contract located at the contract site(s)? 10 Documentation of agreements Do you have access to originals or copies of all contracts and agreements that might affect local PV Unit and/or global PV Unit? Do these safety agreements clearly define delegation of all relevant MAH responsibilities? In answering, please consider ALL types of agreements [in-licensing, out-licensing, co-development, co-marketing, co-promotion, divestment] with both internal and external partners. Does legal department and/or business development Units involve local or global PV Unit in contract negotiations and/or review procedures ? Do you have separate PV agreements? 11 Inquiries from competent authorities Do you have access to written document(s) that describe how you respond to urgent safety inquiries from competent authorities? In answering, please consider both internal and external partners. 12 Heterogeneous reporting requirements Do you have access to written document(s) that describe how you handle products for which the reporting procedures differ from the local PV Unit process, e.g. narcotics, mutual recognition or decentralised procedure products, third party manufactured products? 13 Products and responsibilities Do you have access to an up-to-date list of ALL medical products of your company? Do you have access to an up-to-date list of all products for which you have any reporting responsibility within the company? Do you have access to an up-to-date list of all products for which you have any reporting responsibility to the local (national) competent authority? Do you have an up-to-date list of all products for which a risk management plan is performed by your company? Can you describe the process used to ensure that these lists are kept current (including when there is a change in status of a product)? Can you provide the name of department(s) outside of global PV Unit that you work with in this regard? Can you produce these lists in either electronic or paper form if required? 14 Data mining Do you have access to an up-to-date list of all the active ingredients for which the company is MAH and/or which are marketed or developed by the company? Can you describe how these lists are kept current? Do you have access to an up-to-date list of all active ingredients for which you have any reporting responsibility within the company? Do you have access to an up-to-date list of all active ingredientsfor which you have any reporting responsibility to the local (national) competent authority? Do you have access to written document(s) that describe how the worldwide scientific literature is regularly screened regarding information about the active ingredients for which the company is MAH and/or which are marketed or developed by the company? Does your literature screening process meet the local and/or the international regulatory requirements (periodicity, quality, reporting time frames,…)? Can you provide the name of department(s) outside of local PV Unit that you work with in this regard? If a third party (CRO, licensee, etc.) is involved in this task, are pharmacovigilance responsibilities and accountabilities managed on a regular basis through the use of formal means, such as SOPs, monitoring or audit? Do you have written contractual agreements to describe how the literature screening task is performed? Do you perform audits at the CRO/partners site? In case your company screens external websites (internet, social media etc.) managed, administrated or financed by your company, is there a process in place to ensure a proper assessment of adverse reactions? If yes, how do you select the sources? 15 CCSI Do you have Company Core Safety Information (CCSI) for all of your products? If not, have you defined a Reference Safety Information for all the products missing a CCSI? Do you have written document(s) that describe how the CCSI is used to update your local label? 16 Updating of Labeling Do you have written document(s) that describe how you ensure that you have the latest label (IB, Company Core Label, Local Label) for all products for which you have any reporting responsibility, either within the company or to the local (national) health authority? Can you provide the name of department(s) outside of global PV Unit that you work with in this regard? 17 Information from studies If studies of any type (Phase I-IV, PMS, PASS, Patient Assistance Program, market research program, epidemiological studies, registries, non-interventional trials, etc. for both local and international projects) are currently being performed in your organization, do you have an up-to-date list of all ongoing or planned studies? Can you describe how the list is kept current? Do you receive or have access to all protocols and PV relevant study documents prior to the initiation of a targeted study? Do you have written document(s) that describe how and by whom safety data are captured and reported to local PV Unit for all types of studies? Can you provide the name of department(s) outside of local PV Unit and/or global PV Unit that you work with in this regard? 18 Reconci​liation of data Do you have written document(s) that: Describe how reconciliation is performed between databases (local PV Unit and local CRO study database) Display the schedule of reconciliation between databases, including end-of-study final reconciliation? Can you provide the name of department(s) outside of local PV Unit that you work with in this regard? 19 Spontaneous reports Does your local national regulation/law enable health professionals and/or consumers to call your company directly to report possible ADRs and/or product complaints? If yes, are there a separate Call Center and/or department(s) outside of local PV Unit with responsibility for initial receipt of ADRs and/or product complaints? If yes, are you aware of written document(s) that describe the qualifications for, and training of, the personnel who take the initial possible ADR/product complaint reports there? If yes, are you aware of written document(s) that describe how training records for these individuals are generated and retained there? Do you reconcile the medical information queries received by the Call Center on a regular basis? Do you work with the relevant department(s) on such issues (e.g., perform trainings of Call Center individuals regarding possible ADR reports)? If yes, is the extent of your involvement (e.g. training, tracking, support, etc.) described in written procedures? 20 Collaboration with third parties If a third party (CRO, licensee, etc.) is involved, are pharmacovigilance responsibilities and accountabilities managed on a regular basis through the use of formal means, such as: - Licensing agreements - SOPs - Reconciliation of data - Monitoring - Contact with Global PV Unit - Training - Preparation and submission of Annual Safety reports (ASR) / DSURs Do you have written contractual agreements to describe how the outsourced activity is performed? 21 Receipt of safety related information Are there written document(s) that describe how you ensure that incoming safety related information, either via phone or otherwise, is received by company staff and forwarded to PV staff in due time and correct manner? Are there written document(s), e.g. templates, that describe how these reports are documented and assessed for possible ADRs by local PV Unit? 22 Handling of incoming safety information Do you have written document(s) that describe how the local PV Unit personnel handling incoming safety information (either directly, or forwarded on from Call Center or other non-PV Unit personnel) is handling the collection, processing and reporting of any safety relevant information (e.g. ADR reports) including information about special patients populations (pregnancy, lactation, paediatrics, elderly etc.) exposure or other special situations (e.g., lack of efficacy)? Do you have written document(s) that describe how you ensure that involved personnel handling incoming safety information are requesting lot numbers when capturing information, and are monitoring reports for possible quality defects? Do you have written document(s) describing the responsibilities for quality defects (Qualified Person for Quality - QPQ - versus QPPV) and exchange of relevant information between the responsible parties (PV Unit and QA)? 23 Follow-Up Do you have written document(s) that describe how follow-up of ADR reports and other safety relevant information (please refer to #22)is performed for: - Pre-marketing studies - Post-authorisation spontaneous reports (including consumer reports), and - Post- authorisation studies - Pregnancies - Literature reports - Authority reports - Reports from screening of websites under own management / responsibility or from internet screening? Can you provide the number of follow-up requests per case, for both clinical (pre-marketing) and post-authorisation reports? Do you have a system that you use to track follow-up on cases? If yes, does the tracking system prompt you for all cases requiring follow-up? 23 Monitoring of incoming safety information Do you monitor the number, quality and correct processing of information/day per person (e.g., ADR report; product complaint; inquiry) in: - Dedicated Call Center (if one exists) - Medical Information - Local PV Unit If yes, can you describe the process? Do you perform a regular testing? If no, would you be able to get the information (e.g. metrics) quickly in the case of an internal or external audit or inspection? 25 Differentiation of inquiries Do you have a written document(s) that describe how to differentiate general inquiries that are determined to be: - ADR reports - Product complaint reports - Product complaint reports with associated ADRs? If yes, can you describe the process? If no, would you be able to get the information quickly in the case of an internal or external audit or inspection? Are employees who receive incoming safety information trained to differentiate product complaints and possible ADRs from general inquiries? 26 Business continuity Do you have written document(s) to describe how you handle incoming safety information during non-business hours (i.e., weekday evenings; weekends; holidays)? Do you have written document(s) that describe how you ensure that safety information received by the company during off-hours (including information being received from contractor or other partners [e.g., poison control centers; marketing partners]) is appropriately forwarded to the responsible PV Unit? Do these specifically include a formal reconciliation process? Can you provide the name of department(s) outside of local PV Unit and/or global PV Unit and/or entities outside of your company that you work with in this regard? Does a complementary process exist for product complaints? If yes, can you provide the name of the non-PV Unit department(s) that have responsibility? 27 Serious ADR collection Do you have a standard form for capturing serious ADRs? If yes, does it conform to international standards? 28 Medical review Do you have written document(s) that describe how you ensure that all PV relevant medical information including possible ADR reports get appropriate medical review? Do you have written document(s) that describe the qualification necessary to qualify as medical reviewers? Are the reviewers trained appropriately, do they receive periodic refresher training? As long as more than one medical reviewer is performing this task, how do you ensure that the assessment process is reproducible? Do you assess the results of medical review? Do you perform rater testings? If yes, do you have written document(s) that describe these testings and the consequences derived from the results ? 29 General ADR management Do you have written document(s) that describe the ADR collection, evaluation, processing and reporting? Do these materials comply with global company and local regulatory requirements? Are these materials controlled (i.e. version control, conforming to controlled document SOPs, etc.)? Are employees systematically trained on their content? Do you monitor the compliance to reporting requirements? 30 Local ADR reporting Does your local PV Unit group report directly to the local competent authority? If no, can you provide the name of the department(s) or personnel at your company that performs this function? Can you describe your local competent authority's requirements for ADR reporting, in particular noting: - Any deviations from ICH, EU, or other international standards as to timeframes, definitions, or other factors for expedited reporting of ADRs - Any limitations on contact with reporting health professionals or consumers - Any limitations on obtaining follow-up information from initial reporters - Any procedures by which you obtain ADR reports from the local competent authority Do you have written process, procedures, or structure in place to meet these requirements? Beyond the local competent authority's requirements for ADR reporting, have you made any formal (written) agreements with the authority on ADR reporting processes? 31 Reporting Formats Are you using a format other than the international CIOMS I form for reporting to the local competent authority? If yes, is the process for quality checks (MedDRA coding, translation, etc.) between the CIOMS I form and the local reporting format defined and documented? 32 Periodic Reporting Are aggregate reports such as PSURs or DSURs submitted to the local competent authority? If local PV Unit doesn't report directly, can you provide the name of the department(s) that performs this activity? Do you have written document(s) that describe: - How PSURs are meeting regulatory reporting timeframes - How PSURs are compiled by the different departments/functions within a MAH (e.g. sales, marketing, medical,…)? - Who is responsible for signing and submission the PSUR and if there any back-up procedures in place - How PSURs are adapting regulatory reporting timeframes (e.g., to local or EU Harmonised Birth Dates) - How PSURs are meeting quality requirements of the local competent authority (e.g. review by a medically qualified person and/or the QPPV) - Review and/or approval by the QPPV - How the PSURs are appropriately created and submitted by partner organizations? If a third party (CRO, licensee, etc.) is involved in this task, are PV responsibilities and accountabilities managed on a regular basis through the use of formal means, such as SOPs, monitoring or audits? Do you monitor the compliance of PSUR submission? 33 Technical infrastructure for electronic reporting Are you generating ADR reports for regulatory reporting through an electronic system? If yes, is the electronic tool validated (including documentation)? If yes, can you provide validation documentation at your site? Do you have written document(s) that describe how you track all adverse reactions collected and reported? Do you have sufficient IT support (e.g. for system maintenance, disaster recovery)? Do you have written document(s) that describe who is responsible for data entry, data approval and archiving? 34 Risk communication Do you have experience in the handling of risk communications? If not, do you perform mock recalls on a regular basis? Do you have written document(s) that describe how you handle the following situations: - Dissemination of a Direct Healthcare Professional Communication (“Dear Doctor letter”) or local Healthcare Professional Information tools (e.g., in Germany “Rote Hand-Brief”) - Requirement for additional safety precautions - Decision to not market a product - Crisis management including product recalls (including information of the local competent authorities) - Public relations issues - Product quality issues 35 Standard Operating Procedures (SOPs) Is there a person responsible to identify the need of local PV SOPs (e.g. to meet local requirements) ? As long as local PV SOPs are in place is there a process to ensure that they are compliant with the global PV requirements (e.g. when local PV SOPs are written in local languages) ? Do you have local PV SOPs in place that align with global PV SOPs covering topics such as: - SOP maintenance - Spontaneous Reporting - Serious Unexpected ADR Reporting - Follow-Up - Periodic Safety Reporting - Data entry conventions - MedDRA coding - Handling of product quality complaints - SOPs currently requested by the national competent authorities (e.g. back-up procedures) If there is any conflict between international and local regulatory reporting requirements, do your written local process(es), procedure(s), structure(s), or document(s) describe the local regulatory reporting requirements, and how you are satisfying both the local and global requirements? Do you have access to global PV SOPs (on-line) and back-up mechanism for obtaining them if the online system is not available to you? If not, can you describe how you keep current global PV SOPs and where they are maintained? 36 Archiving policy Do you have written document(s) that describe your local paper retention policy (e.g., which documents are archived)? Is this material consistent with the (local) legal requirements? Is this material consistent with the internal global requirements? Do you have a local SOP(s) that covers archiving of PV Unit-related documents? Can you describe where aggregate safety reports (e.g., PSURs) are archived within your company? Do you have written document(s) that describe your electronic archiving policy (e.g., which documents are archived)? Are the respective systems validated? 37 Archiving facilities Are all case file materials (including adverse event/reaction reports) maintained, e.g. in a fire/water/pest resistant, secure area? Is access to the file materials limited to certain personnel, and is access documented (single document level) ? 38 Data protection policy Do you have written document(s) that describe your local data protection policy? Is this material consistent with the local legal requirements? Is this material consistent with the internal global requirements? 39 IT infrastructure Does your Local company have a local and/or Global PV Unit database? Does your Local company have access (read-only, write) to a Global PV Unit database? If there is no direct access to a Global PV Unit database, can you ensure that requests from Regulatory Authorities are answered in due time? Do you have other electronic tools used e.g., for your (local) archiving, case tracking or compliance reporting ? Are they validated ? Can you gain access to validation documentation at your site? Does your Local company have IT support (e.g., regarding maintenance, disaster recovery addressed in Service Level Agreements) ? 40 Translations Do you have written document(s) that describe how you handle translation of PV related documents in terms of: - From your local language to English (if they are different) - From English to local language (if they are different) - CVs for translator/certificate indicating certified translator Do you perform quality checks regarding translations ? Do you have a back-up process for translations in place ? 41 Audit Is there a prospective audit schedule covering the whole PV systems in place? Do you audit all relevant entities (including CROs) that are involved in the above mentioned PV activities and processes? Do you have written document(s) that describe this task? Is the qualification and the training of the auditors determined? 42 Quality assurance Do you have written document(s) that covers e.g., self inspections, deviation handling, compliance checks? Do you have written document(s) that covers review of corrective and preventive action processes and documentation? 43 Signal managment Do you have written document(s) that covers Signal detection and management? Do you have a database, which is able to generate signals? If yes, is the signal detection tool validated? Does the person responsible for signal detection and assessment appropriately qualified? Do you have an appropriate data set, which allow you for a quantitative method for Signal detection (complex statistical tool) If yes, do you have written document(s) that define the threshold of reactions to be recognised as a signal 44 Risk management system Do you have written procedures in place describing your risk management system? Do you have access to a list of Risk Management Plans (ref 13)? Do you have written document(s) that describe on generation of RMPs? Do you have written document(s) that describe how to implement RMPs locally? Do the RMPs contain the requirement for assessing the effectiveness of the risk minimisation measures? � Written Documents in this checklist shall refer to written process(es), procedure(s), structure(s), or document(s) 1 PAGE page 3 of 14

See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2012. Reproduction is authorised provided the source is acknowledged. 22 June 2012 EMA/541760/2011 Guideline on good pharmacovigilance practices (GVP) Module I – Pharmacovigilance systems and their quality systems Draft finalised by the Agency in collaboration with Member States and submitted to ERMS FG 19 January 2012 Draft agreed by ERMS FG 24 January 2012 Draft adopted by Executive Director 20 February 2012 Released for consultation 21 February 2012 End of consultation (deadline for comments) 18 April 2012 Revised draft finalised by the Agency in collaboration with Member States 20 June 2012 Revised draft agreed by ERMS FG 21 June 2012 Revised draft adopted by Executive Director as final 22 June 2012 Date for coming into effect 2 July 2012 Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 2/25 Table of contents I.A. Introduction ......................................................................................... 4 I.B. Structures and processes ...................................................................... 4 I.B.1. Pharmacovigilance system .................................................................................. 4 I.B.2. Quality, quality objectives, quality requirements and quality system ........................ 5 I.B.3. Quality cycle...................................................................................................... 5 I.B.4. Overall quality objectives for pharmacovigilance .................................................... 5 I.B.5. Principles for good pharmacovigilance practices ..................................................... 5 I.B.6. Responsibilities for the quality system within an organisation .................................. 6 I.B.7. Training of personnel for pharmacovigilance .......................................................... 7 I.B.8. Facilities and equipment for pharmacovigilance ...................................................... 7 I.B.9. Specific quality system procedures and processes .................................................. 8 I.B.9.1. Compliance management by marketing authorisation holders ............................... 8 I.B.9.2. Compliance management by competent authorities ............................................. 8 I.B.10. Record management ......................................................................................... 9 I.B.11. Documentation of the quality system ................................................................ 10 I.B.11.1. Additional quality system documentation by marketing authorisation holders ...... 11 I.B.11.2. Additional quality system documentation by competent authorities .................... 11 I.B.11.3. Critical pharmacovigilance processes and business continuity ............................ 11 I.B.12. Monitoring of the performance and effectiveness of the pharmacovigilance system and its quality system ............................................................................................... 12 I.B.13. Preparedness planning for pharmacovigilance in public health emergencies ........... 13 I.C. Operation of the EU network ............................................................... 13 I.C.1. Overall pharmacovigilance responsibilities of the applicant and marketing authorisation holder in the EU ........................................................................................................ 13 I.C.1.1. Responsibilities of the marketing authorisation holder in relation to the qualified person responsible for pharmacovigilance in the EU ...................................................... 14 I.C.1.2. Qualifications of the qualified person responsible for pharmacovigilance in the EU . 16 I.C.1.3. Role of the qualified person responsible for pharmacovigilance in the EU .............. 16 I.C.1.4. Specific quality system processes of the marketing authorisation holder in the EU . 17 I.C.1.5. Quality system requirements for pharmacovigilance tasks subcontracted by the marketing authorisation holder ................................................................................... 18 I.C.2. Overall pharmacovigilance responsibilities within the EU regulatory network ............ 19 I.C.2.1. Role of the competent authorities in Member States .......................................... 20 I.C.2.2. Role of the European Commission ................................................................... 21 I.C.2.3. Role of the European Medicines Agency ............................................................ 21 I.C.2.3.1. General role of the Agency and the role of the Agency’s secretariat .................. 21 I.C.2.3.2. Role of the Pharmacovigilance Risk Assessment Committee (PRAC) .................. 22 I.C.2.3.3. Role of the Committee for Medicinal Products for Human Use (CHMP) ............... 22 I.C.2.3.4. Role of the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) ...................................................................................... 22 I.C.2.4. Specific quality system processes of the quality systems of competent authorities in Member States and the Agency .................................................................................. 23 I.C.2.5. Quality system requirements for pharmacovigilance tasks delegated or transferred by competent authorities in Member States .................................................................. 24 Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 3/25 I.C.2.6. Transparency of the quality system of the EU regulatory network ........................ 24 I.C.3. Data protection in the EU .................................................................................. 24 I.C.4. Preparedness planning in the EU for pharmacovigilance in public health emergencies25 Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 4/25 I.A. Introduction This Module contains guidance for the establishment and maintenance of quality assured pharmacovigilance systems for marketing authorisation holders, competent authorities of Member States and the Agency. How the systems of these organisations interact while undertaking specific pharmacovigilance processes is described in each respective Module of GVP. The definition of a pharmacovigilance system is provided in Article 1 of Directive 2001/83/EC as a system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in Title IX and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. The Agency likewise maintains a pharmacovigilance system to fulfil its pharmacovigilance activities. For performing their pharmacovigilance activities, marketing authorisation holders, competent authorities of Member States and the Agency shall establish and use quality systems that are adequate and effective for this performance. The legal requirement for quality systems was introduced by Directive 2010/84/EU amending Directive 2001/83/EC (the latter is referenced as DIR) and Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 (the latter is referenced as REG) to strengthen pharmacovigilance in the EU. The minimum requirements of these quality systems are set out in the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC (the Implementing Regulation is referenced as IR). While there has to be compliance with these legal requirements, the implementation of a quality system should be adapted to the respective organisation. By following the overall quality objectives in I.B.4. and the guiding principle in I.B.5. to meet the needs of patients, healthcare professionals and the public in relation to the safety of medicines, the application of the quality system should be adapted to how crucial each pharmacovigilance task is for fulfilling the quality objectives for each medicinal product covered by a quality system. The guidance on quality systems in this Module is consistent with the general principles of the ISO 9000 Standards on good quality management practices, specifically the ISO 9001-2008 Standards on quality management systems, issued by the International Organization for Standardization (ISO). The general application of quality management to pharmacovigilance systems is described under I.B. and requirements specific to the operation of the EU network in I.C.. In this Module, all applicable legal requirements are referenced in the way explained in the GVP Introductory Cover Note and are usually identifiable by the modal verb “shall”. Guidance for the implementation of legal requirements is provided using the modal verb “should”. I.B. Structures and processes I.B.1. Pharmacovigilance system A pharmacovigilance system is defined as a system used by an organisation to fulfil its legal tasks and responsibilities in relation to pharmacovigilance and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance [DIR Art 1(28d)]. A pharmacovigilance system, like any system, is characterised by its structures, processes and outcomes. For each specific pharmacovigilance process, including its necessary structures, a dedicated Module is included in GVP. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 5/25 I.B.2. Quality, quality objectives, quality requirements and quality system For the purpose of GVP, which provides guidance on structures and processes of a pharmacovigilance system, the quality of a pharmacovigilance system can be defined as all the characteristics of the system which are considered to produce, according to estimated likelihoods, outcomes relevant to the objectives of pharmacovigilance. In general terms, quality is a matter of degree and can be measured. Measuring if the required degree of quality has been achieved necessitates pre-defined quality requirements. Quality requirements are those characteristics of a system that are likely to produce the desired outcome, or quality objectives. The overall quality objectives for pharmacovigilance systems are provided under I.B.4.. Specific quality objectives and quality requirements for the specific structures and processes of the pharmacovigilance systems are provided in each Module of GVP as appropriate. The quality system is part of the pharmacovigilance system and consists of its own structures and processes. It shall cover organisational structure, responsibilities, procedures, processes and resources of the pharmacovigilance system as well as appropriate resource management, compliance management and record management [IR Art 8(2)]. I.B.3. Quality cycle The quality system shall be based on all of the following activities: • quality planning: establishing structures and planning integrated and consistent processes; • quality adherence: carrying out tasks and responsibilities in accordance with quality requirements ; • quality control and assurance: monitoring and evaluating how effectively the structures and processes have been established and how effectively the processes are being carried out; and • quality improvements: correcting and improving the structures and processes where necessary [IR Art 8(3)]. I.B.4. Overall quality objectives for pharmacovigilance The overall quality objectives of a pharmacovigilance system are: • complying with the legal requirements for pharmacovigilance tasks and responsibilities; • preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure; • promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public; and • contributing to the protection of patients’ and public health. I.B.5. Principles for good pharmacovigilance practices With the aim of fulfilling the overall quality objectives in I.B.4., the following principles should guide the design of all structures and processes as well as the conduct of all tasks and responsibilities: • The needs of patients, healthcare professionals and the public in relation to the safety of medicines should be met. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 6/25 • Upper management should provide leadership in the implementation of the quality system and motivation for all staff members in relation to the quality objectives. • All persons within the organisation should be involved in and support the pharmacovigilance system on the basis of task ownership and responsibility in a degree according to their tasks and assigned responsibilities. • All persons involved with the entire organisation should engage in continuous quality improvement following the quality cycle in I.B.3.. • Resources and tasks should be organised as structures and processes in a manner that will support the proactive, risk-proportionate, continuous and integrated conduct of pharmacovigilance. • All available evidence on the risk-benefit balance of medicinal products should be sought and all relevant aspects, which could impact on the risk-benefit balance and the use of a product, should be considered for decision-making. • Good cooperation should be fostered between marketing authorisation holders, competent authorities, public health organisations, patients, healthcare professionals, learned societies and other relevant bodies in accordance with the applicable legal provisions. I.B.6. Responsibilities for the quality system within an organisation A sufficient number of competent and appropriately qualified and trained personnel shall be available for the performance of pharmacovigilance activities [IR Art 10(1), Art 14(1)]. Their responsibility should include adherence to the principles defined in I.B.5.. For the purpose of a systematic approach towards quality in accordance with the quality cycle (see I.B.3.), managerial staff (i.e. staff with management responsibilities) in any organisation should be responsible for: • ensuring that the organisation documents the quality system as described in I.B.11.; • ensuring that the documents describing the quality system are subject to document control in relation to their creation, revision, approval and implementation; • ensuring that adequate resources are available and that training is provided (see I.B.7.); • ensuring that suitable and sufficient premises, facilities and equipment are available (see I.B.8.); • ensuring adequate compliance management (see I.B.9.); • ensuring adequate record management (see I.B.10.); • reviewing the pharmacovigilance system including its quality system at regular intervals in risk- based manner to verify its effectiveness (see I.B.12.) and introducing corrective and preventive measures where necessary; • ensuring that mechanisms exist for timely and effective communication, including escalation processes of safety concerns relating to medicinal products within an organisation; • identifying and investigating concerns arising within an organisation regarding suspected non- adherence to the requirements of the quality and pharmacovigilance systems and taking corrective, preventive and escalation action as necessary; • ensuring that audits are performed (see I.B.12.). Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 7/25 In relation to the management responsibilities described above, upper management within an organisation should provide leadership through: • motivating all staff members, based on shared values, trust and freedom to speak and act with responsibility and through recognition of staff members’ contributions within the organisation; and • assigning roles, responsibilities and authorities to staff members according to their competencies and communicating and implementing these throughout the organisation. For competent authorities, all persons involved in the procedures and processes of the quality system established for the performance of pharmacovigilance activities shall be responsible for the good functioning of that quality system and shall ensure a systematic approach towards quality and towards the implementation and maintenance of the quality system [IR Art 8(5)]. I.B.7. Training of personnel for pharmacovigilance Achieving the required quality for the conduct of pharmacovigilance processes and their outcomes by an organisation is intrinsically linked with the availability of a sufficient number of competent and appropriately qualified and trained personnel (see I.B.6.). All personnel involved in the performance of pharmacovigilance activities shall receive initial and continued training [IR Art 10(3), Art 14(2)]. For marketing authorisation holders, this training shall relate to the roles and responsibilities of the personnel [IR Art 10(3)]. The organisation shall keep training plans and records for documenting, maintaining and developing the competences of personnel [IR Art 10(3), Art 14(2)]. Training plans should be based on training needs assessment and should be subject to monitoring. The training should support continuous improvement of relevant skills, the application of scientific progress and professional development and ensure that staff members have the appropriate qualifications, understanding of relevant pharmacovigilance requirements as well as experience for the assigned tasks and responsibilities. All staff members of the organisation should receive and be able to seek information about what to do if they become aware of a safety concern. There should be a process in place within the organisation to check that training results in the appropriate levels of understanding and conduct of pharmacovigilance activities for the assigned tasks and responsibilities, or to identify unmet training needs, in line with professional development plans agreed for the organisations as well as the individual staff members. Adequate training should also be considered by the organisation for those staff members to whom no specific pharmacovigilance tasks and responsibilities have been assigned but whose activities may have an impact on the pharmacovigilance system or the conduct of pharmacovigilance. Such activities include but are not limited to those related to clinical trials, technical product complaints, medical information, terminologies, sales and marketing, regulatory affairs, legal affairs and audits. Appropriate instructions on the processes to be used in case of urgency, including business continuity (see I.B.11.3.), shall be provided by the organisation to their personnel [IR Art 10(4), Art 14(3)]. I.B.8. Facilities and equipment for pharmacovigilance Achieving the required quality for the conduct of pharmacovigilance processes and their outcomes is also intrinsically linked with appropriate facilities and equipment used to support the processes. Facilities and equipment should include office space, information technology (IT) systems and (electronic) storage space. They should be located, designed, constructed, adapted and maintained to suit their intended purpose in line with the quality objectives for pharmacovigilance (see I.B.4.) and Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 8/25 also be available for business continuity (see I.B.11.3.). Facilities and equipment which are critical for the conduct of pharmacovigilance (see I.B.11.3.) should be subject to appropriate checks, qualification and/or validation activities to prove their suitability for the intended purpose. There should be processes in place to keep awareness of the valid terminologies (see Module VI) in their valid versions and to keep the IT systems up-to-date accordingly. I.B.9. Specific quality system procedures and processes I.B.9.1. Compliance management by marketing authorisation holders For the purpose of compliance management, marketing authorisation holders shall have specific quality system procedures and processes in place in order to ensure the following: • the continuous monitoring of pharmacovigilance data, the examination of options for risk minimisation and prevention and that appropriate measures are taken by the marketing authorisation holder [IR Art 11(1)(a)] (see Modules IX and XII); • the scientific evaluation of all information on the risks of medicinal products as regards patients’ or public health, in particular as regards adverse reactions in human beings arising from use of the product within or outside the terms of its marketing authorisation or associated with occupational exposure [IR Art 11(1)(b)] (see Modules VI, VII, VIII, IX); • the submission of accurate and verifiable data on serious and non-serious adverse reactions to the competent authorities within the legally required time-limits [IR Art 11(1)(c)] (see Modules VI and IX); • the quality, integrity and completeness of the information submitted on the risks of medicinal products, including processes to avoid duplicate submissions and to validate signals [IR Art 11(1)(d)] (see Modules V, VI, VII, VIII and IX); • effective communication by the marketing authorisation holder with competent authorities, including communication on new or changed risks (see Module XII and XV), the pharmacovigilance system master file (see Module II), risk management systems (see Module V), risk minimisations measures (see Modules V and XVI), periodic safety update reports (see Module VII), corrective and preventive actions (see Modules II, III and IV) and post-authorisation safety studies (see Module VIII) [IR Art 11(1)(e]; • the update of product information by the marketing authorisation holder in the light of scientific knowledge [IR Art 11(1)(f)] (see Module XII); • appropriate communication of relevant safety information to healthcare professionals and patients (see Module XII and XV) [IR Art 11(1)(g)]. I.B.9.2. Compliance management by competent authorities For the purpose of compliance management, competent authorities shall establish specific quality system procedures and processes in order to achieve all of the following objectives: • ensuring the evaluation of the quality, including completeness, of pharmacovigilance data submitted [IR Art 15(1)(a)]; • ensuring the assessment of pharmacovigilance data and its processing in accordance with the legal timelines [IR Art 15(1)(b)]; • ensuring independence in the performance of pharmacovigilance activities [IR Art 15(1)(c)]; Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 9/25 • ensuring effective communication with patients, healthcare professionals, marketing authorisation holders and the general public [IR Art 15(1)(d)]; • conducting inspections, including pre-authorisation inspections [IR Art 15(1)(f)]. Independence in the performance of pharmacovigilance activities is interpreted in the sense that all regulatory decisions on medicinal products should be taken in the sole interest of patients’ and public health. I.B.10. Record management The organisation shall record all pharmacovigilance information and ensure that it is handled and stored so as to allow accurate reporting, interpretation and verification of that information [IR Art 12(1), Art 16(1)]. A record management system shall be put in place for all documents used for pharmacovigilance activities, ensuring their retrievability as well as traceability of the measures taken to investigate safety concerns, of the timelines for those investigations and of decisions on safety concerns, including their date and the decision-making process [IR Art 12(1), Art 16(1)]. The record management system should support: • the management of the quality of pharmacovigilance data, including their completeness, accuracy and integrity; • timely access to all records; • effective internal and external communication; and • the retention of documents relating to the pharmacovigilance systems and the conduct of pharmacovigilance for individual medicinal products, in accordance with the applicable retention periods. In addition, marketing authorisation holders shall establish mechanisms enabling the traceability and follow-up of adverse reaction reports [IR Art 12(1)]. In this context, it should be ensured that the fundamental right to personal data protection is fully and effectively guaranteed in all pharmacovigilance activities in conformity with legal provisions. The purpose of safeguarding public health constitutes a substantial public interest and consequently the processing of personal data should be justified if identifiable personal data are processed only where necessary and only where the parties involved assess this necessity at every stage of the pharmacovigilance process (IR Recital 17). As part of a record management system, specific measures should therefore be taken at each stage in the storage and processing of pharmacovigilance data to ensure data security and confidentiality. This should involve strict limitation of access to documents and to databases to authorised personnel respecting the medical and administrative confidentiality of the data. There should be appropriate structures and processes in place to ensure that pharmacovigilance data and records are protected from destruction during the applicable record retention period. The record management system should be described in a record management policy. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 10/25 I.B.11. Documentation of the quality system All elements, requirements and provisions adopted for the quality system shall be documented in a systematic and orderly manner in the form of written policies and procedures, such as quality plans, quality manuals and quality records [IR Art 8(4)]. A quality plan documents the setting of quality objectives and sets out the processes to be implemented to achieve them. A procedure is a specified way to carry out a process and may take the format of a standard operating procedure and other work instruction or quality manual. A quality manual documents the scope of the quality system, the processes of the quality system and the interaction between the two. A quality record is a document stating results achieved or providing evidence of activities performed. In order to have a systematic approach, the organisation should define in advance: • quality objectives specific to their organisations in accordance with the overall quality objectives provided under I.B.4. and the structure- and process-specific quality objectives in accordance with each Module of GVP; and • methods for monitoring the effectiveness of the pharmacovigilance system (see I.B.12.). The quality system shall be documented by: • documents on organisational structures and assignments of tasks to personnel (see I.B.11.1. and I.B.11.2.); • training plans and records (see I.B.7.) [IR Art 10(3), Art 14(2)]; • instructions for the compliance management processes (see I.B.9.) [IR Art 11(1), Art 15(1)]; • appropriate instructions on the processes to be used in case of urgency, including business continuity (see I.B.11.3.) [IR Art 10(4), Art 14(3)]; • performance indicators where they are used to continuously monitor the good performance of pharmacovigilance activities [IR Art 9(1)]; • reports of quality audits and follow-up audits, including their dates and results [IR Art 13(2), Art 17(2)]. Training plans and records shall be kept and made available for audit and inspection [IR Art 10(3), Art 14(2)]. It is recommended that the documentation of the quality system also includes: • the methods of monitoring the efficient operation of the quality system and, in particular, its ability to fulfil the quality objectives; • a record management policy; • records created as a result of pharmacovigilance processes which demonstrate that key steps for the defined procedures have been taken; • records and reports relating to the facilities and equipment including functionality checks, qualification and validation activities which demonstrate that all steps required by the applicable requirements, protocols and procedures have been taken; • records to demonstrate that deficiencies and deviations from the established quality system are monitored, that corrective and preventive actions have been taken, that solutions have been Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 11/25 applied to deviations or deficiencies and that the effectiveness of the actions taken has been verified. I.B.11.1. Additional quality system documentation by marketing authorisation holders In addition to the quality system documentation in accordance with I.B.11., marketing authorisation holders shall document: • their human resource management in the pharmacovigilance system master file (PSMF) (see Module II) [IR Art 2(5)(b)]; • job descriptions defining the duties of the managerial and supervisory staff [IR Art 10(2)]; • an organisational chart defining the hierarchical relationships of managerial and supervisory staff [IR Art 10(2)]; • instructions on critical processes (see I.B.11.3.) in the pharmacovigilance system master file (PSMF) (see Module II); and • their record management system in the pharmacovigilance system master file (PSMF) (see Module II) [IR Art 2(5)(c)]. It is recommended that the documentation of the quality system additionally includes the organisational structures and assignments of tasks, responsibilities and authorities to all personnel directly involved in pharmacovigilance tasks. For the requirements of documenting the quality system in the pharmacovigilance system master file (PSMF) or its annexes, see Module II. I.B.11.2. Additional quality system documentation by competent authorities In addition to the quality system documentation in accordance with I.B.11., the organisational structures and the distribution of tasks and responsibilities shall be clear and, to the extent necessary, accessible [IR Art 14(1)]. It is recommended that the documentation of the quality system additionally includes the organisational structures and assignments of tasks, responsibilities and authorities to all personnel directly involved in pharmacovigilance tasks. Contact points shall be established [IR Art 14(1)], in particular to facilitate interaction between competent authorities, marketing authorisation holders and persons reporting information on the risks of medicinal products as regards patients’ or public health. I.B.11.3. Critical pharmacovigilance processes and business continuity The following pharmacovigilance processes should be considered as critical include: • continuous safety profile monitoring and benefit-risk evaluation of authorised medicinal products; • establishing, assessing and implementing risk management systems and evaluating the effectiveness of risk minimisation; Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 12/25 • collection, processing, management, quality control, follow-up for missing information, coding, classification, duplicate detection, evaluation and timely electronic transmission of individual case safety reports (ICSRs) from any source; • signal management; • scheduling, preparation (including data evaluation and quality control), submission and assessment of periodic safety update reports; • meeting commitments and responding to requests from competent authorities, including provision of correct and complete information; • interaction between the pharmacovigilance and product quality defect systems; • communication about safety concerns between marketing authorisation holders and competent authorities, in particular notifying changes to the risk-benefit balance of medicinal products; • communicating information to patients and healthcare professionals about changes to the risk- benefit balance of products for the aim of safe and effective use of medicinal products; • keeping product information up-to-date with the current scientific knowledge, including the conclusions of the assessment and recommendations from the applicable competent authority; • implementation of variations to marketing authorisations for safety reasons according to the urgency required. Business continuity plans should be established in a risk-based manner and should include: • provisions for events that could severely impact on the organisation’s staff and infrastructure in general or on the structures and processes for pharmacovigilance in particular; and • back-up systems for urgent exchange of information within an organisation, amongst organisations sharing pharmacovigilance tasks as well as between marketing authorisation holders and competent authorities. I.B.12. Monitoring of the performance and effectiveness of the pharmacovigilance system and its quality system Processes to monitor the performance and effectiveness of a pharmacovigilance system and its quality system should include: • reviews of the systems by those responsible for management; • audits; • compliance monitoring; • inspections; • evaluating the effectiveness of actions taken with medicinal products for the purpose of minimising risks and supporting their safe and effective use in patients. The organisation may use performance indicators to continuously monitor the good performance of pharmacovigilance activities [IR Art 9(1)] in relation to the quality requirements. The quality requirements for each pharmacovigilance process are provided in each Module of GVP as appropriate. The requirements for the quality system itself are laid out in this Module and its effectiveness should be monitored by managerial staff, who should review the documentation of the quality system (see I.B.11.) at regular intervals, with the frequency and the extent of the reviews to be determined in a Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 13/25 risk-based manner. Pre-defined programmes for the review of the system should therefore be in place. Reviews of the quality system should include the review of standard operating procedures and work instructions, deviations from the established quality system, audit and inspections reports as well as the use of the indicators referred to above. Risk-based audits of the quality system shall be performed at regular intervals to ensure that it complies with the requirements for the quality system, the human resource management, the compliance management, the record management and the data retention and to ensure its effectiveness [IR Art 13(1), Art 17(1)]. Audits of the quality system should include audit of the pharmacovigilance system which is the subject of the quality system. The methods and processes for the audits are described in Module IV. In relation to the pharmacovigilance system of a marketing authorisation holder, a report shall be drawn up on the results for each quality audit and any follow-up audits be sent to the management responsible for the matters audited [IR Art 13(2)]. The report should include the results of audits of organisations or persons the marketing authorisation holder has delegated tasks to, as these are part of the marketing authorisation holder‘s pharmacovigilance system. For competent authorities, the audit report shall be sent to the management responsible for the matters audited [IR Art 17(2)]. As a consequence of the monitoring of the performance and effectiveness of a pharmacovigilance system and its quality system (including the use of audits), corrective and preventive measures should be implemented when deemed necessary. In particular as a consequence of audits, corrective action(s), including a follow-up audit of deficiencies, shall be taken where necessary [IR Art 13(2), Art 17(2)]. Additionally, the competent authorities should have in place arrangements for monitoring the compliance of marketing authorisations holders with legally required pharmacovigilance tasks and responsibilities. They shall further ensure compliance with the legal requirements by means of conducting inspections of marketing authorisation holders [DIR Art 111(1)] (see Module III). Guidance on compliance monitoring for each pharmacovigilance process is provided in each Module of GVP as appropriate. Requirements and methods for evaluating the effectiveness of actions taken upon medicinal products for the purpose of minimising risks and supporting the safe and effective use of medicines in patients are described in Module XVI. I.B.13. Preparedness planning for pharmacovigilance in public health emergencies Any pharmacovigilance system should be adaptable to public health emergencies and preparedness plans should be developed as appropriate. For preparedness planning in the EU, see I.C.4.. I.C. Operation of the EU network I.C.1. Overall pharmacovigilance responsibilities of the applicant and marketing authorisation holder in the EU The marketing authorisation holder in the EU is responsible for the respective pharmacovigilance tasks and responsibilities laid down in Directive 2001/83/EC, Regulation (EC) No 726/2004 and the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC in order to assure responsibility and liability for its authorised medicinal products and to ensure that appropriate action can be taken, when necessary. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 14/25 For this purpose, the marketing authorisation holder shall operate a pharmacovigilance system [DIR 104(1)] and shall establish and use a quality system that is adequate and effective for performing its pharmacovigilance activities [IR Art 8(1)]. There may be circumstances where a marketing authorisation holder may establish more than one pharmacovigilance system, e.g. specific systems for particular types of products (e.g. vaccines, products available without medical prescription). A description of the pharmacovigilance system shall be developed by the applicant for a marketing authorisation in the format of a pharmacovigilance system master file (PSMF) and be maintained by the marketing authorisation holder for all authorised medicinal products (see Module II). The applicant or the marketing authorisation holder is also responsible for developing and maintaining product- specific risk management systems (see Module V). Guidance on the structures and processes on how the marketing authorisation holder should conduct the pharmacovigilance tasks and responsibilities is provided in the respective GVP Modules. I.C.1.1. Responsibilities of the marketing authorisation holder in relation to the qualified person responsible for pharmacovigilance in the EU As part of the pharmacovigilance system, the marketing authorisation holder shall have permanently and continuously at its disposal an appropriately qualified person responsible for pharmacovigilance in the EU (QPPV) [DIR Art 104(3)(a)]. The marketing authorisation holder shall submit the name and contact details of the QPPV to the competent authorities in Member States and the Agency [DIR Art 104(3) last paragraph]. Changes to this information should be submitted in accordance with Regulation (EC) No 1234/2008 on variations to the terms of marketing authorisation and the Communication from the Commission - Guideline on the Details of the Various Categories of Variations to the Terms of Marketing Authorisations for Medicinal Products for Human Use and Veterinary Medicinal Products1. The duties of the QPPV shall be defined in a job description [IR Art 10(2)]. The hierarchical relationship of the QPPV shall be defined in an organisational chart together with those of other managerial and supervisory staff [IR Art 10(2)]. Information relating to the QPPV shall be included in the pharmacovigilance systems master file (PSMF) [IR Art 2(1)] (see Module II). Each pharmacovigilance system can have only one QPPV. A QPPV may be employed by more than one marketing authorisation holder, for a shared or for separate pharmacovigilance systems or may fulfil the role of QPPV for more than one pharmacovigilance system of the same marketing authorisation holder, provided that the QPPV is able to fulfil all obligations. In addition to the QPPV, competent authorities in Member States are legally provided with the option to request the nomination of a pharmacovigilance contact person at national level reporting to the QPPV. Reporting in this context relates to pharmacovigilance tasks and responsibilities and not necessarily to line management. A contact person at national level may also be nominated as the QPPV. The marketing authorisation holder shall ensure that the QPPV has sufficient authority to influence the performance of the quality system and the pharmacovigilance activities of the marketing authorisation holder [IR Art 10(2)]. The marketing authorisation holder should therefore ensure that the QPPV has 1 See Volume 2C of the Rules Governing Medicinal Products in the EU; http://ec.europa.eu/health/documents/eudralex/vol- 2/index_en.htm http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 15/25 access to the pharmacovigilance system master file (PSMF) as well as authority over it and is notified of any changes to it in accordance with Module II (see I.C.1.3). The authority over the pharmacovigilance system and the PSMF should allow the QPPV to implement changes to the system and to provide input into risk management plans (see Module V) as well as into the preparation of regulatory action in response to emerging safety concerns (see Module XII). Overall, the marketing authorisation holder should ensure that structures and processes are in place, so that the QPPV can fulfil the responsibilities listed in I.C.1.3.. In order to do this, the marketing authorisation holder should ensure that mechanisms are in place so that the QPPV receives all relevant information and that the QPPV can access all information the QPPV considers relevant, in particular on: • emerging safety concerns and any other information relating to the benefit-risk evaluation of the medicinal products covered by the pharmacovigilance system; • ongoing or completed clinical trials and other studies the marketing authorisation holder is aware of and which may be relevant to the safety of the medicinal products; • information from sources other than from the specific marketing authorisation holder, e.g. from those with whom the marketing authorisation holder has contractual arrangements; and • the procedures relevant to pharmacovigilance which the marketing authorisation holder has in place at every level in order to ensure consistency and compliance across the organisation. The outcome of the regular reviews of the quality system referred to in I.B.6. and I.B.12. and the measures introduced should be communicated by the managerial staff to the QPPV. Compliance information should be provided to the QPPV on a periodic basis. Such information may also be used to provide assurance to the QPPV that commitments in the framework of risk management plans and post-authorisation safety systems are being adhered to. The managerial staff should also inform the QPPV of scheduled pharmacovigilance audits. The QPPV should be able to trigger an audit where appropriate. The managerial staff should provide the QPPV with a copy of the corrective and preventive action plan following each audit relevant to the pharmacovigilance system the QPPV is responsible for, so that the QPPV can assure that appropriate corrective actions are implemented. In particular with regard to its adverse reaction database (or other systems to collate adverse reaction reports), the marketing authorisation holder should implement a procedure to ensure that the QPPV is able to obtain information from the database, for example, to respond to urgent requests for information from the competent authorities or the Agency, at any time. If this procedure requires the involvement of other personnel, for example database specialists, then this should be taken into account in the arrangements made by the marketing authorisation holder for supporting the QPPV outside of normal working hours. When a marketing authorisation holder intends to expand its product portfolio, for example, by acquisition of another company or by purchasing individual products from another marketing authorisation holder, the QPPV should be notified as early as possible in the due diligence process in order that the potential impact on the pharmacovigilance system can be assessed and the system be adapted accordingly. The QPPV may also have a role in determining what pharmacovigilance data should be requested from the other company, either pre- or post-acquisition. In this situation, the QPPV should be made aware of the sections of the contractual arrangements that relate to responsibilities for pharmacovigilance activities and safety data exchange and have the authority to request amendments. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 16/25 When a marketing authorisation holder intends to establish a partnership with another marketing authorisation holder, organisation or person that has a direct or indirect impact on the pharmacovigilance system, the QPPV should be informed early enough and be involved in the preparation of the corresponding contractual arrangements (see I.C.1.5.) so that all necessary provisions relevant to the pharmacovigilance system are included. I.C.1.2. Qualifications of the qualified person responsible for pharmacovigilance in the EU The marketing authorisation holder shall ensure that the QPPV has acquired adequate theoretical and practical knowledge for the performance of pharmacovigilance activities [IR Art 10(1)]. The QPPV should have skills for the management of pharmacovigilance systems as well as expertise or access to expertise in relevant areas such as medicine, pharmaceutical sciences as well as epidemiology and biostatistics. Where the QPPV has not completed basic medical training in accordance with Article 24 of Directive 2005/36/EC, the marketing authorisation holder shall ensure that the QPPV is assisted by a medically trained person (i.e. in accordance with Article 24 of Directive 2005/36/EC) and this assistance shall be duly documented [IR Art 10(1)]. The expectation is that the applicant or marketing authorisation holder will assess the qualification of the QPPV prior to appointment by, for example, reviewing university qualifications, knowledge of EU pharmacovigilance requirements and experience in pharmacovigilance. The applicant or marketing authorisation holder should provide the QPPV with training in relation to its pharmacovigilance system, which is appropriate for the role prior to the QPPV taking up the position and which is appropriately documented. Consideration should be given to additional training, as needed, of the QPPV in the medicinal products covered by the pharmacovigilance system. I.C.1.3. Role of the qualified person responsible for pharmacovigilance in the EU The qualified person responsible for pharmacovigilance in the EU (QPPV) is a natural2 person. The QPPV appointed by the marketing authorisation holder shall be appropriately qualified (see I.C.1.2.) and shall be at the marketing authorisation holder’s disposal permanently and continuously (see I.C.1.1.) [DIR Art 104 (3)(a)]. The QPPV shall reside and operate in the EU [DIR Art 104 (3) last paragraph]. Following European Economic Area (EEA) agreements, the QPPV may also reside and operate in Norway, Iceland or Liechtenstein. Back-up procedures in the case of absence of the QPPV shall be in place [IR Art 2(1)(d)] and should be accessible through the QPPV’s contact details. The QPPV should ensure that the back-up person has all necessary information to fulfil the role. The QPPV shall be responsible for the establishment and maintenance of the marketing authorisation holder’s pharmacovigilance system [DIR Art 104 (3) last paragraph] and therefore shall have sufficient authority to influence the performance of the quality system and the pharmacovigilance activities [IR Art 10(2)] and to promote, maintain and improve compliance with the legal requirements [IR Art 2(1)(a)]. Hence, the QPPV should have access to the pharmacovigilance system master file (PSMF) (see Module II) and be in a position of authority to ensure and to verify that the information contained in the PSMFis an accurate and up-to-date reflection of the pharmacovigilance system under the QPPV’s responsibility. In relation to the medicinal products covered by the pharmacovigilance system, specific additional responsibilities of the QPPV should include: 2 A natural person is a real human being, as distinguished from a corporation which is often treated at law as a fictitious person. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 17/25 • having an overview of medicinal product safety profiles and any emerging safety concerns; • having awareness of any conditions or obligations adopted as part of the marketing authorisations and other commitments relating to safety or the safe use of the products; • having awareness of risk minimisation measures; • being aware of and having sufficient authority over the content of risk management plans; • being involved in the review and sign-off of protocols of post-authorisation safety studies conducted in the EU or pursuant to a risk management plan agreed in the EU; • having awareness of post-authorisation safety studies requested by a competent authority including the results of such studies; • ensuring conduct of pharmacovigilance and submission of all pharmacovigilance-related documents in accordance with the legal requirements and GVP; • ensuring the necessary quality, including the correctness and completeness, of pharmacovigilance data submitted to the competent authorities in Members States and the Agency; • ensuring a full and prompt response to any request from the competent authorities in Members States and from the Agency for the provision of additional information necessary for the benefit- risk evaluation of a medicinal product; • providing any other information relevant to the benefit-risk evaluation to the competent authorities in Members States and the Agency; • providing input into the preparation of regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals); • acting as a single pharmacovigilance contact point for the competent authorities in Member States and the Agency on a 24-hour basis and also as a contact point for pharmacovigilance inspections. This responsibility for the pharmacovigilance system means that the QPPV has oversight over the functioning of the system in all relevant aspects, including its quality system (e.g. standard operating procedures, contractual arrangements, database operations, compliance data regarding quality, completeness and timeliness of expedited reporting and submission of periodic update reports, audit reports and training of personnel in relation to pharmacovigilance). Specifically for the adverse reaction database, if applicable, the QPPV should be aware of the validation status of the database, including any failures that occurred during validation and the corrective actions that have been taken to address the failures. The QPPV should also be informed of significant changes that are made to the database (e.g. changes that could have an impact on pharmacovigilance activities). The QPPV may delegate specific tasks, under supervision, to appropriately qualified and trained individuals, for example, acting as safety experts for certain products, provided that the QPPV maintains system oversight and overview of the safety profiles of all products. Such delegation should be documented. I.C.1.4. Specific quality system processes of the marketing authorisation holder in the EU In applying the requirements set out in I.B.9.1. in the EU, the marketing authorisation holder shall put in place the following additional specific quality system processes for ensuring: • the submission of adverse reaction data to EudraVigilance within the legal timelines [IR Art 11(c)]; Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 18/25 • the monitoring of the use of terminology referred to in IR Art 25(1) either systematically or by regular random evaluation [IR Art 25(3)]; • the retention of minimum elements of the pharmacovigilance system master file (PSMF) (see IR Art 2 and Module II) as long as the system described in the PSMF exists and for at least further 5 years after it has been formally terminated by the marketing authorisation holder [IR Art 12(2)]; • the retention of pharmacovigilance data and documents relating to individual authorised medicinal products as long as the marketing authorisation exists and for at least further 10 years after the marketing authorisation has ceased to exist [IR Art 12(2)]; • that the product information is kept up-to-date by the marketing authorisation holder in the light of scientific knowledge, including the assessments and recommendations made public via the European medicines web-portal an on the basis of a continuous monitoring by the marketing authorisation holder of information published on the European medicines web-portal [IR Art 11(1)(g)]. The retention periods above apply unless the documents shall be retained for a longer period where EU or national law so requires [IR Art 12(2)]. During the retention period, retrievability of the documents should be ensured. Documents can be retained in electronic format, provided that the electronic system has been appropriately validated and appropriate arrangements exist for system security, access and back-up of data. If documents in paper format are transferred into an electronic format, the transfer process should ensure that all of the information present in the original format is retained in a legible manner and that the media used for storage will remain readable over time. Documents transferred in situations where the business of the marketing authorisation holder is taken over by another organisation should be complete. I.C.1.5. Quality system requirements for pharmacovigilance tasks subcontracted by the marketing authorisation holder The marketing authorisation holder may subcontract certain activities of the pharmacovigilance system to third parties [IR Art 6(1)], i.e. to another organisation or person (where the same requirements apply to a person as for an organisation). This may include the role of the QPPV. The marketing authorisation holder shall nevertheless retain full responsibility for the completeness and accuracy of the pharmacovigilance system master file (PSMF) (see Module II) [IR Art 6(1)]. The ultimate responsibility for the fulfilment of all pharmacovigilance tasks and responsibilities and the quality and integrity of the pharmacovigilance system always remains with the marketing authorisation holder. Where a marketing authorisation holder has subcontracted some tasks of its pharmacovigilance tasks, it shall retain responsibility for ensuring that an effective quality system is applied in relation to those tasks [IR Art 11(2)]. All guidance provided in GVP is also applicable to the other organisation to which the tasks have been subcontracted. When subcontracting tasks to another organisation, the marketing authorisation holder shall draw up subcontracts [IR Art 6(2)] and these should be detailed, up-to-date and clearly document the contractual arrangements between the marketing authorisation holder and the other organisation, describing arrangements for delegation and the responsibilities of each party. A description of the subcontracted activities and/or services shall be included in the pharmacovigilance system master file (PSMF) [IR Art 2(6)] and a list of the subcontracts shall be included in an annex to the PSMF, specifying the product(s) and territory(ies) concerned [IR Art 6(2)] (see Module II). The other Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 19/25 organisation may be subject to inspection at the discretion of the competent or supervisory authority in the relevant Member State. Contractual arrangements should be prepared with the aim of enabling compliance with the legal requirements by each party involved. When preparing contractual arrangements, the marketing authorisation holder should include sufficiently detailed descriptions of the delegated tasks, the related interactions and data exchange, together with, for example, agreed definitions, tools, assignments and timelines. The contractual arrangements should also contain clear information on the practical management of pharmacovigilance as well as related processes, including those for the maintenance of pharmacovigilance databases. Further, they should indicate which processes are in place for checking whether the agreed arrangements are being adhered to on an ongoing basis. In this respect, regular risk-based audits of the other organisation by the marketing authorisation holder or introduction of other methods of control and assessment are recommended. With respect to centrally authorised products, contractual arrangements between different marketing authorisation holders should also be in place in relation to separately authorised medicinal products with the application of Article 82(1) of Regulation (EC) No 726/2004 in order to ensure conduct of pharmacovigilance on the basis of complete worldwide data sets. For responsibilities of the marketing authorisation holder towards the QPPV in this context, see I.C.1.1.. I.C.2. Overall pharmacovigilance responsibilities within the EU regulatory network The competent authorities in Member States and the Agency are responsible for the respective pharmacovigilance tasks and responsibilities imposed on them by Directive 2001/83/EC, Regulation (EC) No 726/2004 and the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC in order to ensure that appropriate action can be taken, when necessary. For this purpose each competent authority in a Member State as well as the Agency shall operate a pharmacovigilance system [DIR 101(1)] and shall establish and use an adequate and effective quality system for performing their pharmacovigilance activities [IR Art 8(1)]. The Agency and the Member States shall cooperate to continuously develop pharmacovigilance systems capable of achieving high standards of public health protection for all medicinal products, regardless of the routes of marketing authorisation, including the use of collaborative approaches, to maximise use of resources available within the EU [REG Art 28e]. The requirement in I.B.11.2. according to which competent authorities shall keep accessible clear descriptions of the organisational structures, assignment of tasks and responsibilities as well as contact points [IR Art 14(1)], should relate to the interaction between competent authorities in Member States, the Agency, the European Commission, marketing authorisation holders and persons reporting information on the risks of medicinal products. Guidance on the structures and processes to enable the competent authorities in Member States and the Agency to conduct the pharmacovigilance tasks and responsibilities is provided in the respective Modules of GVP. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 20/25 I.C.2.1. Role of the competent authorities in Member States Each Member State shall designate a competent authority for the performance of pharmacovigilance [DIR Art 101(3)]. This authority is usually the same as the competent authority responsible for granting national marketing authorisations. Each competent authority in a Member State must operate a pharmacovigilance system for the fulfilment of their pharmacovigilance tasks and their participation in EU pharmacovigilance activities [DIR Art 101(1)]. In this context, the competent authority in a Member State is responsible for the safety monitoring of each medicinal product, independent of its route of authorisation, in the territory of that Member State. In particular, the competent authority in each Member State shall be responsible for monitoring data originating in their territory [IR Art 18(4)]. For nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, the competent authority in a Member State is responsible for granting, varying, suspending and revoking a marketing authorisation. The pharmacovigilance tasks and responsibilities of competent authorities in Member States for each process in relation to such products, are detailed in the respective Modules of GVP. For products authorised through the mutual recognition or the decentralised procedure, one Member State acts as the Reference Member State. For practical reasons, the competent authority of the Reference Member State should coordinate communication with the marketing authorisation holder on pharmacovigilance matters and monitor the compliance of the marketing authorisation holder with legal pharmacovigilance requirements. These arrangements do not replace the legal responsibilities of the marketing authorisation holder with respect to individual competent authorities and the Agency. Nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, may become subject to regulatory procedures at EU level on pharmacovigilance grounds. If a Commission Decision for a nationally authorised product exists as an outcome of such a procedure, the competent authorities in Member States are responsible for the implementation of the Commission Decision and also for its follow-up, unless exceptionally further action by the Agency and the European Commission has been foreseen in the Commission Decision reflecting the outcome of the regulatory procedure (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons). The pharmacovigilance tasks and responsibilities of competent authorities in Member States in relation to centrally authorised products are also detailed in the respective Modules of GVP. They include the collaboration in signal detection (see Module IX) and implementation of Commission Decisions regarding risk management of centrally authorised products addressed to Member States (see Module V). Where urgent action is essential to protect human health or the environment, the competent authority in a Member State, on its own initiative or at the European Commission’s request, may suspend the use of a centrally authorised product in its territory (see Modules XII). Competent authorities in Member States are responsible for pharmacovigilance inspections of organisations in their territory in relation to medicinal products. This is independent of the route of marketing authorisation as well as which competent authority granted the marketing authorisation for the respective medicinal product (see Module III). In relation to the various aspects of the role described above, each Member State’s competent authority should ensure that all pharmacovigilance data are shared between competent authorities in other Member States, the European Commission and the Agency for each process in accordance with the legislation and the guidance in the respective GVP Modules. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 21/25 I.C.2.2. Role of the European Commission The European Commission is the competent authority for medicinal products authorised through the centralised procedure and is responsible for granting, varying, suspending and revoking their marketing authorisations by adoption of Commission Decisions on the basis of Opinions adopted by the Committee for Medicinal Products for Human Use (CHMP) (see I.C.2.3.3.). Further, the European Commission adopts Commission Decisions in relation to nationally authorised medicinal products subject to regulatory procedures at EU level, including on pharmacovigilance grounds. The European Commission may also initiate such procedures (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons). I.C.2.3. Role of the European Medicines Agency I.C.2.3.1. General role of the Agency and the role of the Agency’s secretariat The role of the Agency is to coordinate the monitoring of medicinal products for human use authorised in the EU and to provide advice on the measures necessary to ensure their safe and effective use, in particular, by coordinating the evaluation and implementation of legal pharmacovigilance requirements and the monitoring of such implementation. The tools established and maintained by the Agency for the coordination are presented in the GVP Modules for each process. The Agency provides coordination and technical, scientific and administrative support to the Pharmacovigilance Risk Assessment Committee (PRAC) (see I.C.2.3.2.) and the Committee for Medicinal Products for Human Use (CHMP) (see I.C.2.3.3.) and coordination and technical and administrative support to the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) (see I.C.2.3.4.), as well as coordination between the committees and the CMDh. Pharmacovigilance for centrally authorised products is conducted by the Agency with the involvement of the Rapporteurs, the PRAC and the CHMP. The Agency should take the lead for communicating with the marketing authorisation holders of centrally authorised products. The respective responsibilities for each pharmacovigilance process are detailed in the GVP Modules. For nationally authorised products, the Agency coordinates regulatory procedures at EU level on pharmacovigilance grounds through providing support to the CMDh and CHMP (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons). The Agency also cooperates with other EU bodies as necessary. Specific pharmacovigilance tasks of the Agency include: • running the EudraVigilance database [REG Art 57(d)]; • monitoring selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances [REG Art 27] (see Module VI); • running processes for the EU coordination of the assessment of periodic safety update reports (see Module VII) and oversight of post-authorisation safety studies (see Module VIII); • tasks relating to signal detection [REG Art 28a(1)(c), IR Art 18-24] (see Module IX); • tracking of follow-up of safety concerns and other pharmacovigilance matters at EU level (see Module XII); Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 22/25 • assisting Member States with the rapid communication of information on safety concerns to healthcare professionals and coordinating the safety announcements of the national competent authorities [REG Art 57(e)] (see Module XV); • distributing appropriate information on safety concerns to the general public, in particular by setting up and maintaining the European medicines web-portal [REG Art 57(f)] (see Module XV); • coordination of safety announcements between national competent authorities for active substances contained in medicinal products authorised in more than one Member State, including providing timetables for the publication of information [DIR 106a(3)] (see Module XV); and specifically in relation to centrally authorised products: • assessing updates to risk management systems [REG Art 28a(1)(b)] (see Module V); • monitoring the outcome of risk minimisation measures [REG Art 28a(1)(a)] (see Module XVI). I.C.2.3.2. Role of the Pharmacovigilance Risk Assessment Committee (PRAC) The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for providing recommendations to the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) on any question relating to pharmacovigilance activities in respect of medicinal products for human use and on risk management systems, including the monitoring of the effectiveness of those risk management systems [REG Art 56(1)(aa)]. The Details on the responsibilities for each process are presented in the respective GVP Modules. The Mandate and Rules of Procedure of the PRAC are published on the Agency’s website3. I.C.2.3.3. Role of the Committee for Medicinal Products for Human Use (CHMP) The Committee for Medicinal Products for Human Use (CHMP) is responsible for evaluating applications and formulating Opinions serving as a basis for granting, varying, suspending or withdrawing marketing authorisations for centrally authorised products. The CHMP also prepares Opinions on safety concerns emerging after a marketing authorisation has been granted for centrally authorised products or, for nationally authorised products, including those through the mutual recognition or the decentralised procedure, in the framework of regulatory procedures at EU level in which at least one centrally authorised product is involved (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons), procedures for the assessment of periodic safety update reports (PSURs) (see Module VII) and procedures for post-authorisation safety studies (see Module VIII). For questions related to pharmacovigilance activities and risk management systems, the CHMP relies on the recommendations from the Pharmacovigilance Risk Assessment Committee (PRAC). The specific responsibilities of each party for each pharmacovigilance process are described in the GVP Modules. The Rules of Procedure of the CHMP are published on the Agency’s website4. I.C.2.3.4. Role of the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) The Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) is responsible for examining any question relating to marketing authorisations for medicinal products authorised through the mutual recognition or the decentralised procedure and questions on the 3 http://www.ema.europa.eu 4http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000095.jsp&murl=menus/abou t_us/about_us.jsp&mid=WC0b01ac0580028c7a http://www.ema.europa.eu/ http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000095.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028c7a http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000095.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028c7a Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 23/25 variation of marketing authorisations granted by the Member States as well as questions arising for nationally authorised products from assessments of periodic safety update reports (see Module VII), post-authorisation safety studies (see Module VIII) and during regulatory procedures at EU level. The CMDh shall reach a position, based on a PRAC recommendation, on regulatory procedures at EU level when only nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, are involved [DIR Art 107k](see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons). The responsibilities of the CMDh for each pharmacovigilance process are described in the respective GVP Modules. The Rules of Procedure of the CMDh and the Functions and Tasks for CMDh are published on the HMA website5. I.C.2.4. Specific quality system processes of the quality systems of competent authorities in Member States and the Agency In applying the requirements set out in I.B.9.2. in the EU, the competent authorities in Member States and the Agency shall put in place the following additional specific quality system processes for: • monitoring and validating the use of terminology referred to in IR Art 25(1), either systematically or by regular random evaluation [IR Art 25(3)]; • assessing and processing pharmacovigilance data in accordance with the timelines provided by legislation [IR Art 15(1)(b)]; • ensuring effective communication within the EU regulatory network in accordance with the provisions on safety announcements in Article 106a of Directive 2001/83/EC [IR Art 15(1)(d)] (see Module XV); • guarantying that competent authorities in Member States and the Agency inform each other and the European Commission of their intention to make announcements relating to the safety of a medicinal product or an active substance contained in a medicinal product authorised in several Member State (see Modules XII and XV) [IR Art 15(1)(e)]; • arranging for the essential documents describing their pharmacovigilance systems to be kept as long as the system exists and for at least further 5 years after they have been formally terminated [IR Art 16(2)]; • ensuring that pharmacovigilance data and documents relating to individual authorised medicinal products are retained as long as the marketing authorisation exists or for at least further 10 years after the marketing authorisation has expired [IR Art 16(2)]. In this context, documents relating to a medicinal product include documents of a reference medicinal product where this is applicable. The retention periods above apply unless the documents shall be retained for a longer period where EU or national law so requires [IR Art 16(2)]. During the retention periods referred to above, retrievability of the documents should be ensured. Documents can be retained in electronic format, provided that the electronic system has been appropriately validated and appropriate arrangements exist for system security, access and back-up of data. If pharmacovigilance documents in paper format are transferred into an electronic format, the transfer process should ensure that all of the information present in the original format is retained in a legible manner and that the media used for storage will remain readable over time. 5 http://www.hma.eu/205.html http://www.hma.eu/205.html Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 24/25 The legal requirements for record management (see I.B.10.) imply accessibility to the records from within the EU, preferably at a single point. In addition to the above, competent authorities in Member States shall establish procedures for collecting and recording all suspected adverse reactions that occur in their territory (see Module VI) [IR Art 15(2)]. In addition to the above, the Agency shall establish procedures for literature monitoring in accordance with Article 27 of Regulation (EC) No 726/2004 (see Module VI) [IR Art 15(3)]. In addition to the quality system documentation in accordance with I.B.11. and I.B.11.2., competent authorities in Member States and the Agency shall clearly determine, and to the extent necessary, keep accessible the organisational structures and the distribution of tasks and responsibilities [IR Art 14(1)] as well as establish contact points [IR Art 14(1)], in particular to facilitate interaction between competent authorities in Member States, the Agency, marketing authorisation holders and persons reporting information on the risks of medicinal products as regards patients’ or public health. Quality audits of the Member States’ and Agency ‘s pharmacovigilance systems (see I.B.12.) shall be performed according to a common methodology [IR Art 17(1)]. The results of audits shall be reported by competent authorities in Member States in accordance with Article 101(2) of Directive 2001/83/EC and by the Agency in accordance with Article 28f of Regulation (EC) No 726/2004 (see Module IV). I.C.2.5. Quality system requirements for pharmacovigilance tasks delegated or transferred by competent authorities in Member States A competent authority in a Member State may delegate any pharmacovigilance task to another Member State subject to a written agreement of the latter Member State [DIR Art 103]. The written agreement should be reflected by exchange of letters, defining the scope of the delegation. A competent authority in a Member State may transfer any or all of the pharmacovigilance tasks to another organisation, but the ultimate responsibility for the fulfilment of all pharmacovigilance tasks and responsibilities and the quality and integrity of the pharmacovigilance system always remains with the competent authority in a Member State. Where tasks are transferred to another organisation, the competent authority in a Member State should ensure that the tasks are subject to a quality system compliant with the legal requirements applicable to their own organisation. I.C.2.6. Transparency of the quality system of the EU regulatory network The European Commission (EC) shall publish every three years a report on the performance of pharmacovigilance based on the reports submitted by the competent authorities in Member States (first EC report due on 21 July 2015) and by the Agency (first EC report due on 2 January 2014) on the results of their regular pharmacovigilance system audits (see Module IV) [DIR Art 101(2), Art 108b, REG Art 28f, Art 29]. I.C.3. Data protection in the EU All legal requirements of the IR, including those relating to the record management described in I.B.10., shall apply without prejudice to the obligations of national competent authorities and marketing authorisation holders relating to their processing of personal data under Directive 95/46/EC or the obligations of the Agency relating to its processing of personal data under Regulation (EC) No 45/2001 [IR Art 39]. Guideline on good pharmacovigilance practices (GVP) – Module I EMA/541760/2011 Page 25/25 I.C.4. Preparedness planning in the EU for pharmacovigilance in public health emergencies The pharmacovigilance systems of marketing authorisation holders, competent authorities in Member States and the Agency should be adaptable to public health emergencies. Preparedness plans should be developed as appropriate (see I.B.13.). A public health emergency is a public health threat duly recognised either by the World Health Organization (WHO) or the Community in the framework of Decision No. 2119/98/EC of the European Parliament and of the Council. Pharmacovigilance requirements for public health emergencies should be considered by the competent authorities in Member States, the European Commission and the Agency on a case-by-case basis and appropriately notified to marketing authorisation holders and the public. The Agency publishes its notifications on the Agency’s website. I.A. Introduction I.B. Structures and processes I.B.1. Pharmacovigilance system I.B.2. Quality, quality objectives, quality requirements and quality system I.B.3. Quality cycle I.B.4. Overall quality objectives for pharmacovigilance I.B.5. Principles for good pharmacovigilance practices I.B.6. Responsibilities for the quality system within an organisation I.B.7. Training of personnel for pharmacovigilance I.B.8. Facilities and equipment for pharmacovigilance I.B.9. Specific quality system procedures and processes I.B.9.1. Compliance management by marketing authorisation holders I.B.9.2. Compliance management by competent authorities I.B.10. Record management I.B.11. Documentation of the quality system I.B.11.1. Additional quality system documentation by marketing authorisation holders I.B.11.2. Additional quality system documentation by competent authorities I.B.11.3. Critical pharmacovigilance processes and business continuity I.B.12. Monitoring of the performance and effectiveness of the pharmacovigilance system and its quality system I.B.13. Preparedness planning for pharmacovigilance in public health emergencies I.C. Operation of the EU network I.C.1. Overall pharmacovigilance responsibilities of the applicant and marketing authorisation holder in the EU I.C.1.1. Responsibilities of the marketing authorisation holder in relation to the qualified person responsible for pharmacovigilance in the EU I.C.1.2. Qualifications of the qualified person responsible for pharmacovigilance in the EU I.C.1.3. Role of the qualified person responsible for pharmacovigilance in the EU I.C.1.4. Specific quality system processes of the marketing authorisation holder in the EU I.C.1.5. Quality system requirements for pharmacovigilance tasks subcontracted by the marketing authorisation holder I.C.2. Overall pharmacovigilance responsibilities within the EU regulatory network I.C.2.1. Role of the competent authorities in Member States I.C.2.2. Role of the European Commission I.C.2.3. Role of the European Medicines Agency I.C.2.3.1. General role of the Agency and the role of the Agency’s secretariat I.C.2.3.2. Role of the Pharmacovigilance Risk Assessment Committee (PRAC) I.C.2.3.3. Role of the Committee for Medicinal Products for Human Use (CHMP) I.C.2.3.4. Role of the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) I.C.2.4. Specific quality system processes of the quality systems of competent authorities in Member States and the Agency I.C.2.5. Quality system requirements for pharmacovigilance tasks delegated or transferred by competent authorities in Member States I.C.2.6. Transparency of the quality system of the EU regulatory network I.C.3. Data protection in the EU I.C.4. Preparedness planning in the EU for pharmacovigilance in public health emergencies

9 April 2013 EMA/816573/2011 Rev 1* Guideline on good pharmacovigilance practices (GVP) Module II – Pharmacovigilance system master file (Rev 1) Draft of first version finalised by the Agency in collaboration with Member States 19 January 2012 Draft agreed by ERMS FG 24 January 2012 Draft adopted by Executive Director 20 February 2012 Released for consultation 21 February 2012 End of consultation (deadline for comments) 18 April 2012 Revised draft of first version finalised by the Agency in collaboration with Member States 20 June 2012 Revised draft agreed by ERMS FG 21 June 2012 Revised draft adopted by Executive Director as final 22 June 2012 Date for coming into effect 2 July 2012 Draft Revision 1* finalised by the Agency in collaboration with Member States 21 February 2013 Draft Revision 1 agreed by ERMS FG 8 March 2013 Draft Revision 1 adopted by Executive Director as final 9 April 2013 Date for coming into effect of Revision 1 12 April 2013 *Note: Revision 1 contains the following: - a correction of the text with regard to the requirements for herbal and homeopathic medicinal products in II.B.2.1. on page 5; - an emphasis on the requirements of IR Art 2 in a first new sentence of II.B.4. on page 8; - emphasis on legal references to IR Art 3 and IR Art 5(4) in II.3.4.8. on page 14. See websites for contact details European Medicines Agency www.ema.europa.eu Heads of Medicines Agencies www.hma.eu The European Medicines Agency is an agency of the European Union © European Medicines Agency and Heads of Medicines Agencies, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents II.A. Introduction ........................................................................................ 3 II.B. Structures and processes .................................................................... 3 II.B.1. Objectives ........................................................................................................ 4 II.B.2. Registration and maintenance ............................................................................ 4 II.B.2.1. Summary of the applicant’s pharmacovigilance system ....................................... 4 II.B.2.2. Location ........................................................................................................ 5 II.B.2.3. Registration ................................................................................................... 6 II.B.2.4. Transfers of responsibilities for the pharmacovigilance system master file ............. 6 II.B.3. The representation of pharmacovigilance systems ................................................. 7 II.B.4. Information to be contained in the pharmacovigilance system master file ................ 8 II.B.4.1. PSMF section on qualified person responsible for pharmacovigilance (QPPV) .......... 8 II.B.4.2. PSMF section on the organisational structure of the marketing authorisation holder 9 II.B.4.3. PSMF section on the sources of safety data ..................................................... 10 II.B.4.4. PSMF section on computerised systems and databases ..................................... 10 II.B.4.5. PSMF section on pharmacovigilance processes ................................................. 11 II.B.4.6. PSMF section on pharmacovigilance system performance .................................. 11 II.B.4.7. PSMF section on quality system ..................................................................... 12 II.B.4.8. Annex to the PSMF ....................................................................................... 13 II.B.5 Change control, logbook, versions and archiving .................................................. 15 II.B.6. Pharmacovigilance system master file presentation ............................................. 16 II.B.6.1. Format and layout ........................................................................................ 16 II.C. Operation of the EU network ............................................................. 18 II.C.1. Responsibilities ............................................................................................... 18 II.C.1.1. Marketing authorisation holders and applicants ................................................ 18 II.C.1.2. National competent authorities ...................................................................... 18 II.C.1.3. The European Medicines Agency .................................................................... 19 II.C.2. Accessibility of the pharmacovigilance system master file .................................... 19 II.C.3. Transparency ................................................................................................. 20 Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 2/20 II.A. Introduction The legal requirement for marketing authorisation holders to maintain and make available upon request a pharmacovigilance system master file (PSMF) was introduced by Directive 2010/84/EU amending Directive 2001/83/EC (Recitals (7) and (35), Article 23(4), Article 104(3)(b)) and Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 (Recitals (22) and (25), Article 16(4), to harmonise and strengthen the conduct of pharmacovigilance activities in the EU. The pharmacovigilance system master file definition is provided in Article 1(28e) of Directive 2001/83/EC and the minimum requirements for its content and maintenance are set out in the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC (the Implementing Regulation is referenced as IR). The detailed requirements provided by the Commission Implementing Regulation are further supported by the guidance in this Module of the Good Vigilance Practice(s). The pharmacovigilance system master file shall be located either at the site in the EU where the main pharmacovigilance activities of the marketing authorisation holder are performed or at the site in the EU where the qualified person responsible for pharmacovigilance operates [IR Art 7(1)]. It is a requirement of the marketing authorisation application that summary information about the pharmacovigilance system is submitted to the competent authorities. This summary includes information on the location of the pharmacovigilance system master file (see II.B.2.1). There is no requirement for variations for changes in the content of the pharmacovigilance system master file. This Module provides detailed guidance regarding the requirements for the pharmacovigilance system master file, including its maintenance, content and associated submissions to competent authorities, applicable from July 2012, during the transition period (as described in Article 2 of Directive 2010/84/EU and Article 3 of Regulation (EU) No 1235/2010), and after 2015. In this Module, all applicable legal requirements are referenced in the way explained in the GVP Introductory Cover Note and are usually identifiable by the modal verb “shall”. Guidance for the implementation of legal requirements is provided using the modal verb “should”. II.B. Structures and processes The pharmacovigilance system master file is a legal requirement in the EU. This guidance concerns the requirements for the pharmacovigilance system master file and is applicable for any medicinal product authorised in the EU, irrespective of the marketing authorisation procedure. The required content and management of the pharmacovigilance system master file applies irrespective of the organisational structure of a marketing authorisation holder, including any subcontracting or delegation of activities, or their location. Irrespective of the location of other activities, the qualified person for pharmacovigilance (QPPV’s) residence, the location at which he/she carries out his/her tasks and the pharmacovigilance system master file location must be within the EU. Following European Economic Area (EEA) agreements, the QPPV may also reside and operate in Norway, Iceland or Liechtenstein. The content of the pharmacovigilance system master file should reflect global availability of safety information for medicinal products authorised in the EU, with information on the pharmacovigilance system not just confined to local or regional activities. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 3/20 II.B.1. Objectives The pharmacovigilance system master file shall describe the pharmacovigilance system and support/document its compliance with the requirements. As well as fulfilling the requirements for a pharmacovigilance system master file laid down in the legislation and guidance, it shall also contribute to the appropriate planning and conduct of audits by the applicant or marketing authorisations holder(s), the fulfilment of supervisory responsibilities of the QPPV, and of inspections or other verification of compliance by national competent authorities. The pharmacovigilance system master file provides an overview of the pharmacovigilance system, which may be requested and assessed by national competent authorities during marketing authorisation application(s) or post-authorisation. Through the production and maintenance of the pharmacovigilance system master file, the marketing authorisation holder and the QPPV should be able to: • gain assurance that a pharmacovigilance system has been implemented in accordance with the requirements; • confirm aspects of compliance in relation to the system; • obtain information about deficiencies in the system, or non-compliance with the requirements; • obtain information about risks or actual failure in the conduct of specific aspects of pharmacovigilance. The use of this information should contribute to the appropriate management of and improvement(s) to the pharmacovigilance system. The requirements for submission of a summary of the marketing authorisation holder’s pharmacovigilance system, provision of the content of pharmacovigilance system master file and the history of changes to the relevant authority(ies) should enable the appropriate co-ordination of inspections by the Agency, and the planning and effective conduct of inspections by national competent authorities, based on a risk assessment approach. Responsibilities, in terms of the pharmacovigilance system master file, for marketing authorisation holders and applicants, national competent authorities and the Agency are described in detail in Section C (see II.C.1.). II.B.2. Registration and maintenance II.B.2.1. Summary of the applicant’s pharmacovigilance system Article 8(3)(ia) of Directive 2001/83/EC requires a summary of the applicant’s pharmacovigilance system to be included in the marketing authorisation application, which shall include the following elements in module 1.8.1 of the dossier: • proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance; • the Member States in which the qualified person resides and carries out his/her tasks; • the contact details of the qualified person; • a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX; • a reference to the location where the pharmacovigilance system master file for the medicinal product is kept. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 4/20 The requirement for submission of a detailed description of the pharmacovigilance system (DDPS) with each marketing authorisation application is no longer applicable. For new applications, the summary of the pharmacovigilance system must be included in the application. As required by Article 16 of Regulation (EC) No 726/2004 and Article 23 of Directive 2001/83/EC, amendments to the particulars or documents referred to in the summary of the applicant’s pharmacovigilance system shall be submitted in accordance with Commission Regulation (EC) No 1234/2008 and the associated Guideline. Applicants for, and holders of simplified registrations of traditional herbal medicinal products are not required to submit a pharmacovigilance system summary, however, they are required to operate a pharmacovigilance system and prepare, maintain and make available on request a pharmacovigilance system master file. For other herbal medicinal products, not falling within the scope of the traditional use registration, the requirements to operate a pharmacovigilance system, to prepare, maintain and make available on request a pharmacovigilance system master file and to submit a summary of the pharmacovigilance system apply. For homeopathic medicinal products registered via the simplified registration procedure the requirements to operate a pharmacovigilance system, to maintain and make available on request a pharmacovigilance system master file and to submit a summary of the pharmacovigilance system do not apply. For other homeopathic medicinal products, not falling within the scope of the simplified registration, the requirements to operate a pharmacovigilance system, to prepare, maintain and make available on request a pharmacovigilance system master file and to submit a summary of the pharmacovigilance system apply. II.B.2.2. Location The pharmacovigilance system master file shall be located within the EU, either at the site where the main pharmacovigilance activities are performed or at the site where the qualified person responsible for pharmacovigilance operates [IR Art 7(1)], irrespective of the format (paper-based or electronic format file). Following European Economic Area (EEA) agreements, the PSMF may also be located in Norway, Iceland or Liechtenstein. Details about the location of the pharmacovigilance system master file are required to be entered in the extended Eudravigilance Medicinal Product Dictionary (XEVMPD), and any change to the location shall be notified immediately to the Agency in order to have the information in the XEVMPD and on the European medicines web-portal referred to in Article 26(1) of Regulation (EC) No 726/2004 updated.[IR Art 4(4), REG Art 57(2)(c)] (see Eudravigilance guidance and EMA website guidance on electronic submission of information on medicines).The required location information for the PSMF is a physical office address of the marketing authorisation holder or a contracted third party. Where the pharmacovigilance system master file is held in electronic form, the location stated must be a site where the data stored can be directly accessed, and this is sufficient in terms of a practical electronic location [IR Art 7(3)]. When determining the main site of pharmacovigilance activity, the marketing authorisation holder should consider the most relevant EU site for the pharmacovigilance system as a whole, since the relative importance of particular activities may vary according to products and fluctuate in the short term. The marketing authorisation holder should have an appropriate rationale for the location decision. In the situation where the main activities take place outside the EU, or where a main site cannot be determined, the location should default to the site where the QPPV operates. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 5/20 II.B.2.3. Registration All pharmacovigilance system master files must be registered in XEVMPD. The MAH shall update the database with the location of the pharmacovigilance system master file for each product, and update the information immediately upon change, as XEVMPD must be correctly populated with the pharmacovigilance system master file location [IR Art 4(4)]. At the time of marketing authorisation application, the applicant should submit electronically the pharmacovigilance system master file location information using the agreed format as referred to in chapter IV, Article 26, paragraph 1(a) of the Commission Implementing Regulation (EU) No 520/2012, and subsequently include in the application, the pharmacovigilance system master file reference number, which is the unique code assigned by the Eudravigilance (EV) system to the master file when the XEVPRM is processed (guidance on electronic submission of information on medicines is published on the EMA website). On grant of a marketing authorisation application, the pharmacovigilance system master file will be linked by the marketing authorisation holder to the EVMPD product code(s). Submission of information about the location of the pharmacovigilance system master file that occurs at times other than a marketing authorisation application or a renewal application must be submitted in accordance with Commission Regulation (EC) No 1234/2008 and the associated Guideline. In order to facilitate the submission of master file location information for more than one product covered by a single pharmacovigilance system (and therefore with a common pharmacovigilance system master file), the variations can be grouped. II.B.2.4. Transfers of responsibilities for the pharmacovigilance system master file The pharmacovigilance system may change with time. Transfer or delegation of responsibilities and activities concerning the master file should be documented (see II.B.4.2. and II.B.4.8.) and managed to ensure that the marketing authorisation holder fulfils their responsibilities. Since a specific QPPV has responsibility for the pharmacovigilance system, changes to the pharmacovigilance system master file should also be notified to the QPPV in order to support their authority to make improvements to the system. The types of changes that should be routinely and promptly notified to the QPPV are: • Updates to the pharmacovigilance system master file or its location that are notified to the competent authorities; • The addition of corrective and/or preventative actions to the pharmacovigilance system master file (e.g. following audits and inspections). The QPPV should also be able to access information about deviations from the processes defined in the quality management system for pharmacovigilance; • Changes to content that fulfil the criteria for appropriate oversight of the pharmacovigilance system (in terms of capacity, functioning and compliance); • Changes in arrangements for the provision of the pharmacovigilance system master file to competent authorities; • Transfer of significant services for pharmacovigilance to a third party (e.g. outsourcing of PSUR production); • Inclusion of products into the pharmacovigilance system for which the QPPV is responsible; • Changes for existing products which may require a change or increased workload in relation to pharmacovigilance activity e.g. new indications, studies or the addition of territories. Any recipient QPPV should explicitly accept the following changes in writing: Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 6/20 • Transfer of responsibility for a pharmacovigilance system to a QPPV. The QPPV should be in a position to ensure and to verify that the information contained in the pharmacovigilance system master file is an accurate and up to date reflection of the pharmacovigilance system under his/her responsibility (see Module I). II.B.3. The representation of pharmacovigilance systems The pharmacovigilance system master file, as per definition in Article 1(28e) of the Directive 2001/83/EC, shall describe the pharmacovigilance system for one or more medicinal products of the marketing authorisation holder. For different categories of medicinal products the marketing authorisation holder may, if appropriate, apply separate pharmacovigilance systems. Each such system shall be described in a separate pharmacovigilance system master file. Those files shall cumulatively cover all medicinal products of the marketing authorisation holder for which a marketing authorisation has been issued in accordance with Directive 2001/83/EC or an authorisation has been granted in accordance with Regulation (EC) No 726/2004. • It is anticipated that there will be circumstances where a single marketing authorisation holder may establish more than one pharmacovigilance system e.g. specific systems for particular types of products (vaccines, consumer health, etc.), or that the pharmacovigilance system may include products from more than one marketing authorisation holder. In either case, a single and specific pharmacovigilance system master file shall be in place to describe each system. • In accordance with Articles 8 and 104 of the Directive 2001/83/EC, a single QPPV shall be appointed to be responsible for the establishment and maintenance of the pharmacovigilance system described in the pharmacovigilance system master file. • Where a pharmacovigilance system is shared by several marketing authorisation holders each marketing authorisation holder is responsible ensuring that a pharmacovigilance system master file exists to describe the pharmacovigilance system applicable for his products. For a particular product(s) the marketing authorisation holder may delegate through written agreement (e.g. to a licensing partner or contractor) part or all of the pharmacovigilance activity for which the marketing authorisation holder is responsible. In this case the pharmacovigilance system master file of the marketing authorisation holder may cross refer to all or part of the pharmacovigilance system master file managed by the system of the party to whom the activity has been delegated subject to agreement on access to that system’s information for the marketing authorisation holder and the authorities. The marketing authorisation holder should be able to assure the content of the referenced file(s) in relation to the pharmacovigilance system applicable to their product(s). Activities for maintaining the pharmacovigilance system master file in a current and accessible state can be delegated. • Where applicable, a list of all pharmacovigilance system master files held by the same marketing authorisation holder shall be provided in the annex (see II.B.4.8.) [IR Art 3(7)]; this includes their location(s), details of the responsible QPPV(s) and the relevant product(s). • Submission of summary information to competent authorities cannot contain multiple locations for a single pharmacovigilance system master file. The address of the location of the pharmacovigilance system master file provided to fulfil the requirement of Article 8(3) of the Directive 2001/83/EC (and within XEVMPD) should be an office address which reflects either the site in the EU where the main pharmacovigilance activities of the marketing authorisation holder are performed or the site where the qualified person responsible for pharmacovigilance operates. This address may be different to that of the applicant/marketing authorisation holder, for example, Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 7/20 a different office of the marketing authorisation holder or when a third party undertakes the main activities. • Similarly, the QPPV details aligned to a product in XEVMPD may be those of a contract QPPV responsible for the pharmacovigilance system for a particular medicinal product, and not necessarily a QPPV directly employed by the marketing authorisation holder. • When delegating any activities concerning the pharmacovigilance system and its master file, the marketing authorisation holder retains ultimate responsibility for the pharmacovigilance system, submission of information about the pharmacovigilance system master file location, maintenance of the pharmacovigilance system master file and its provision to competent authorities upon request [IR Art 6]. Detailed written agreements describing the roles and responsibilities for pharmacovigilance system master file content, submissions and management, as well as to govern the conduct of pharmacovigilance in accordance with the legal requirements, should be in place [IR Art 6]. • When a pharmacovigilance system is shared, it is advised that the partners agree on how to mutually maintain the relevant sections within their own pharmacovigilance system master files. Accessibility of the pharmacovigilance system master file to all the applicable marketing authorisation holder(s), and its provision to competent authorities should be defined in written agreements. It is vital that marketing authorisation holder(s) can gain assurance that the pharmacovigilance system used for its products is appropriate and compliant. II.B.4. Information to be contained in the pharmacovigilance system master file The pharmacovigilance system master file shall contain at least all of the documents listed in Article 2 of the Commission Implementing Regulation (EU) No 520/2012. The pharmacovigilance system master file shall include documents to describe the pharmacovigilance system. The content of the pharmacovigilance system master file should reflect the global availability of safety information for medicinal products authorised in the EU. The content shall be indexed to allow for efficient navigation around the document and follow the modular system described in the following sections and the annex headings described in II.B.6.1. The main principle for the structure of the content of the pharmacovigilance system master file is that the primary topic sections contain information that is fundamental to the description of pharmacovigilance system. Detailed information is required to fully describe the system, and, since this may change frequently, it should be referred to and contained in the Annexes. The control associated with change of content is described in section II.B.5. It is accepted that, where no marketing authorisation (and master file) previously existed in the EU, there may be information that cannot be initially provided, for example, compliance information, however, descriptions of what will be implemented should be provided instead. II.B.4.1. PSMF section on qualified person responsible for pharmacovigilance (QPPV) For the QPPV, contact details shall be provided in the marketing authorisation application [DIR Art 8(3)(ia)] and/or via the XEVMPD. The information relating to the QPPV provided in the PSMF [IR Art 2(1)] shall include: • a description of the responsibilities guaranteeing that the qualified person has sufficient authority over the pharmacovigilance system in order to promote, maintain and improve compliance; Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 8/20 • a summary curriculum vitae with the key information on the role of the qualified person responsible for pharmacovigilance, including proof of registration with the Eudravigilance database; • contact details; • details of back-up arrangements to apply in the absence of the qualified person responsible for pharmacovigilance; and • information relating to the contact person for pharmacovigilance where such a person has been nominated at national level in accordance with Article 104(4) of Directive 2001/83/EC, including contact details. A list of tasks that have been delegated by the qualified person for pharmacovigilance shall also be included in the Annexes (see II.B.4.8.). This should outline the activities that are delegated and to whom, and include the access to a medically qualified person if applicable (Module I and [IR Art 10(1)]). This list may be supplied as a copy of a written procedural document provided the required content is covered. The details provided in relation to the QPPV should also include the description of the QPPV qualifications, experience and registrations relevant to pharmacovigilance (including registration with Eudravigilance). The contact details supplied should include name, postal, telephone, fax and e-mail and represent the usual working address of the QPPV, which may therefore be different to a marketing authorisation holder address. If the QPPV is employed by a third party, even if the usual working address is an office of the marketing authorisation holder, this should be indicated and the name of the company the QPPV works for provided. II.B.4.2. PSMF section on the organisational structure of the marketing authorisation holder A description of the organisational structure of the marketing authorisation holder relevant to the pharmacovigilance system must be provided. The description should provide a clear overview of the company(ies) involved, the main pharmacovigilance departments and the relationship(s) between organisations and operational units relevant to the fulfilment of pharmacovigilance obligations. This should include third parties. Specifically, the pharmacovigilance system master file shall describe: • The organisational structure of the marketing authorisation holder(s), showing the position of the QPPV in the organisation. • The site(s) where the pharmacovigilance functions are undertaken covering individual case safety report collection, evaluation, safety database case entry, periodic safety update report production, signal detection and analysis, risk management plan management, pre- and post- authorisation study management, and management of safety variations to product particulars [IR Art 2(2)]. Diagrams may be particularly useful; the name of the department or third party should be indicated. Delegated activities The pharmacovigilance system master file, where applicable, shall contain a description of the delegated activities and/or services relating to the fulfillment of pharmacovigilance obligations [IR Art 2 (6)]. This includes arrangements with other parties in any country, Worldwide and if applicable, to the pharmacovigilance system applied to products authorised in the Community. Links with other organisations, such as co-marketing agreements and contracting of pharmacovigilance activities should be outlined. A description of the location and nature of contracts and agreements Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 9/20 relating to the fulfilment of pharmacovigilance obligations should be provided. This may be in the form of a list/table to show the parties involved, the roles undertaken and the concerned product(s) and territories. The list should be organised according to; service providers (e.g. medical information, auditors, patient support programme providers, study data management etc.), commercial arrangements (distributors, licensing partners, co-marketing etc.) and other technical providers (hosting of computer systems etc.). Individual contractual agreements shall be made available at the request of national competent authorities and the Agency or during inspection and audit and the list provided in the Annexes (see II.B.4.8.). II.B.4.3. PSMF section on the sources of safety data The description of the main units for safety data collection should include all parties responsible, on a global basis, for solicited and spontaneous case collection for products authorised in the EU. This should include medical information sites as well as affiliate offices and may take the form of a list describing the country, nature of the activity and the product(s) (if the activity is product specific) and providing a contact point (address, telephone and e-mail) for the site. The list may be located in the Annexes of the pharmacovigilance system master file. Information about third parties (licence partners or local distribution/marketing arrangements) should also be included in the section describing contracts and agreements (see II.B.4.2. and II.B.4.8.). Flow diagrams indicating the main stages, timeframes and parties involved may be used. However represented, the description of the process for ICSRs from collection to reporting to competent authorities should indicate the departments and/or third parties involved. For the purposes of inspection and audit of the pharmacovigilance system, sources include data arising from study sources, including any studies, registries, surveillance or support programmes sponsored by the marketing authorisation holder through which ICSRs could be reported. MAHs should be able to produce and make available a list of such sources to support inspection, audit and QPPV oversight. In the interests of harmonisation, it is recommended that the list should be comprehensive for products authorised in the EU, irrespective of indication, product presentation or route of administration. The list should describe, on a worldwide basis, the status of each study/programme, the applicable country(ies), the product(s) and the main objective. It should distinguish between interventional and non-interventional studies and should be organised per active substance. The list should be comprehensive for all studies/programmes and should include ongoing studies/programmes as well as studies/programmes completed in the last two years and may be located in an Annex or provided separately. II.B.4.4. PSMF section on computerised systems and databases The location, functionality and operational responsibility for computerised systems and databases used to receive, collate, record and report safety information and an assessment of their fitness for purpose shall be described in the pharmacovigilance system master file [IR Art 2(3)]. Where multiple computerised systems/databases are used, the applicability of these to pharmacovigilance activities should be described in such a way that a clear overview of the extent of computerisation within the pharmacovigilance system can be understood. The validation status of key aspects of computer system functionality should also be described; the change control, nature of testing, back-up procedures and electronic data repositories vital to pharmacovigilance compliance should be included in summary, and the nature of the documentation available described. For paper- based systems (where an electronic system may only be used for expedited submission of ICSRs), the management of the data, and mechanisms used to assure the integrity and accessibility of the safety data, and in particular the collation of information about adverse drug reactions, should be described. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 10/20 II.B.4.5. PSMF section on pharmacovigilance processes An essential element of any pharmacovigilance system is that there are clear written procedures in place. Module I describes the required minimum set of written procedures for pharmacovigilance. A description of the procedural documentation available (standard operating procedures, manuals, at a global and/or National level etc.), the nature of the data held (e.g. the type of case data retained for ICSRs) and an indication of how records are held (e.g. safety database, paper file at site of receipt) should be provided in the pharmacovigilance system master file. A description of the process, data handling and records for the performance of pharmacovigilance, covering the following aspects shall be included in the pharmacovigilance system master file: • Continuous monitoring of product risk-benefit profile(s) applied and the result of evaluation and the decision making process for taking appropriate measures; this should include signal generation, detection and evaluation. This may also include several written procedures and instructions concerning safety database outputs, interactions with clinical departments etc; • Risk management system(s) and monitoring of the outcome of risk minimisation measures; several departments may be involved in this area and interactions should be defined in written procedures or agreements; • ICSR collection, collation, follow-up, assessment and reporting; the procedures applied to this area should clarify what are local and what are global activities; • PSUR scheduling, production and submission, if applicable (see Module VII); • Communication of safety concerns to consumers, healthcare professionals and the competent authorities; • Implementation of safety variations to the summary of product characteristics (SmPC) and patient information leaflets; procedures should cover both internal and external communications [IR Art 2(4)]. In each area, the marketing authorisation holder should be able to provide evidence of a system that supports appropriate and timely decision making and action. The description must be accompanied by the list of processes referred to in article 11(1) of the Commission Implementing Regulation (EU) No 520/2012 under the topic compliance management, as well as interfaces with other functions. Interfaces with other functions include, but are not limited to, the roles and responsibilities of the QPPV, responding to competent authority requests for information, literature searching, safety database change control, safety data exchange agreements, safety data archiving, pharmacovigilance auditing, quality control and training. The list, which may be located in the Annexes, should comprise the procedural document reference number, title, effective date and document type (for all standard operating procedures, work instructions, manuals etc.). Procedures belonging to service providers and other third parties should be clearly identified. Documents relating to specific local/country procedures need not be listed, but a list may be requested on a per country basis. If no or only some countries use specific local procedures, this should be indicated (and the names of the applicable countries provided). II.B.4.6. PSMF section on pharmacovigilance system performance The pharmacovigilance system master file should contain evidence of the ongoing monitoring of performance of the pharmacovigilance system including compliance of the main outputs of pharmacovigilance. The pharmacovigilance system master file should include a description of the monitoring methods applied and contain as a minimum: Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 11/20 • An explanation of how the correct reporting of ICSRs is assessed. In the annex, figures/graphs should be provided to show the timeliness of 15-day and 90-day reporting over the past year; • A description of any metrics used to monitor the quality of submissions and performance of pharmacovigilance. This should include information provided by competent authorities regarding the quality of ICSR reporting, PSURs or other submissions; • An overview of the timeliness of PSUR reporting to competent authorities in the EU (the annex should reflect the latest figures used by the marketing authorisation holder to assess compliance); • An overview of the methods used to ensure timeliness of safety variation submissions compared to internal and competent authority deadlines, including the tracking of required safety variations that have been identified but not yet been submitted; • Where applicable, an overview of adherence to risk management plan commitments, or other obligations or conditions of marketing authorisation(s) relevant to pharmacovigilance. Targets for the performance of the pharmacovigilance system shall be described and explained. A list of performance indicators must be provided in the Annex to the pharmacovigilance system master file [IR Art 3(6) and Art 9], alongside the results of (actual) performance measurements. II.B.4.7. PSMF section on quality system A description of the quality management system should be provided, in terms of the structure of the organisation and the application of the quality to pharmacovigilance. This shall include: Document and Record Control A description of the archiving arrangements for electronic and/or hardcopy versions of the pharmacovigilance system master file should be provided, as well as an overview of the procedures applied to other quality system and pharmacovigilance records and documents (see also Module I). Procedural documents • A general description of the types of documents used in pharmacovigilance (standards, operating procedures, work instructions etc), the applicability of the various documents at global, regional or local level within the organisation, and the controls that are applied to their accessibility, implementation and maintenance. • Information about the documentation systems applied to relevant procedural documents under the control of third parties. A list of specific procedures and processes related to the pharmacovigilance activities and interfaces with other functions, with details of how the procedures can be accessed [IR Art 2(5)(a)] must be provided, and the detailed guidance for the inclusion of these is in section II.B.4.5. Training • A description of the resource management for the performance of pharmacovigilance activities: − the organisational chart giving the number of people (full time equivalents) involved in pharmacovigilance activities, which may be provided in the section describing the organisational structure (see II.B.4.3) • Information about sites where the personnel are located (this is described under sections II.B.4.2 and II.B.4.3) whereby the sites are provided in the PSMF in relation to the organisation of specific pharmacovigilance activities and in the Annexes which provide the list of site contacts for sources Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 12/20 of safety data. However, a description should be provided in order to explain the training organisation in relation to the personnel and site information; • A summary description of the training concept, including a reference to the location training files. Staff should be appropriately trained for performing pharmacovigilance related activities and this includes not only staff within pharmacovigilance departments but also any individual that may receive safety reports. Auditing Information about quality assurance auditing of the pharmacovigilance system should be included in the pharmacovigilance system master file. A description of the approach used to plan audits of the pharmacovigilance system and the reporting mechanism and timelines should be provided, with a current list of the scheduled and completed audits concerning the pharmacovigilance system maintained in the annex referred to II.B.4.8. [IR Art 3(5)]. This list should describe the date(s) (of conduct and of report), scope and completion status of audits of service providers, specific pharmacovigilance activities or sites undertaking pharmacovigilance and their operational interfaces relevant to the fulfilment of the obligations in the Directive 2001/83/EC, and cover a rolling 5 year period. The pharmacovigilance system master file shall also contain a note associated with any audit where significant findings are raised. This means that the presence of findings that fulfil the EU criteria for major or critical findings must be indicated (see Module IV). The audit report must be documented within the quality system; in the pharmacovigilance system master file it is sufficient to provide a brief description of the corrective and/or preventative action(s) associated with the significant finding, the date it was identified and the anticipated resolution date(s), with cross reference to the audit report and the documented corrective and preventative action plan(s). In the annex, in the list of audits conducted, those associated with unresolved notes in the pharmacovigilance system master file, should be identified. The note and associated corrective and preventative action(s), shall be documented in the pharmacovigilance system master file until the corrective and/or preventative action(s) have been fully implemented, that is, the note is only removed once corrective action and/or sufficient improvement can be demonstrated or has been independently verified [DIR Art 104(2)]. The addition, amendment or removal of the notes must therefore be recorded in the logbook. As a means of managing the pharmacovigilance system, and providing a basis for audit or inspection, the pharmacovigilance system master file should also describe the process for recording, managing and resolving deviations from the quality system. The master file shall also document deviations from pharmacovigilance procedures, their impact and management until resolved [IR Art 4(3)]. This may be documented in the form of a list referencing a deviation report, and its date and procedure concerned. II.B.4.8. Annex to the PSMF An annex to the pharmacovigilance system master file shall contain the following documents: • A list of medicinal products covered by the pharmacovigilance system master file including the name of the medicinal product, the name of the active substance(s), and the Member State(s) in which the authorisation is valid [IR Art 3]; The list of medicinal products authorised in the EU should also include the authorisation number(s) including, per authorisation: Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 13/20 − the type of procedure for authorisation and procedure number (e.g. centrally authorised, nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure); − the Rapporteur country or Reference Member State; − the presence on the market in the EU; − other (non EU) territories where the product is authorised or on the market. The list should be organised per active substance and, where applicable, should indicate what type of product specific safety monitoring requirements exist (for example risk minimisation measures contained in the risk management plan or laid down as conditions of the marketing authorisation, non-standard PSUR periodicity, referral under Article 31 of the Directive 2001/83/EC, or included in the list described in Article 23 of the Regulation (EC) No 726/2004). The monitoring information may be provided as a secondary list. For marketing authorisations that are included in a different pharmacovigilance system, for example, because the MAH has more than one pharmacovigilance system or third party agreements exist to delegate the system, reference to the additional pharmacovigilance system master file(s) should also be provided as a separate list in the Annexes, such that, for a MAH, the entire product portfolio can be related to the set of pharmacovigilance system master files. Where pharmacovigilance systems are shared, all products that utilise the pharmacovigilance system should be included, so that the entire list of products covered by the file is available. The products lists may be presented separately, organised per MAH. Alternatively, a single list may be used, which is supplemented with the name of the MAH(s) for each product, or a separate note can be included to describe the product(s) and the MAH(s) covered; • A list of written policies and procedures for the purpose of complying with Article 11(1) of the Commission Implementing Regulation (EU) 520/2012 [IR Art 3]; • A list of contractual agreements covering delegated activities including the medicinal products and territory(ies) concerned in accordance with Article 6(2) of the Commission Implementing Regulation No 520/2012 (see II.B.4.3.) [IR Art 3]; • A list of tasks that have been delegated by the qualified person for pharmacovigilance [IR Art 3]; • A list of all completed audits, for a period of five years, and a list of audit schedules [IR Art 3]; • Where applicable, a list of performance indicators in accordance with Article 9 of the Commission Implementing Regulation No 520/2012 [IR Art 3]; • Where applicable, a list of other pharmacovigilance system master files held by the same marketing authorisation holder [IR Art 3]; This list should include the pharmacovigilance system master file number(s), and the name of MAH of the QPPV responsible for the pharmacovigilance system used. If the pharmacovigilance system is managed by another party that is not a marketing authorisation holder, the name of the service provider should also be included. • A logbook in accordance with Article 5(4) of the Commission Implementing Regulation No 520/2012 [IR Art 3] and other change control documentation should be included as appropriate. Documented changes shall include at least the date, person responsible for the change and the nature of the change [IR Art 5(4)]. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 14/20 II.B.5 Change control, logbook, versions and archiving It is necessary for marketing authorisation holders to implement change control systems and to have robust processes in place to continuously be informed of relevant changes in order to maintain the pharmacovigilance system master file accordingly. The competent authorities may solicit information about important changes to the pharmacovigilance system, such as, but not limited to: • Changes to the pharmacovigilance safety database(s), which could include a change in the database itself or associated databases, the validation status of the database as well as information about transferred or migrated data; • Changes in the provision of significant services for pharmacovigilance, especially major contractual arrangements concerning the reporting of safety data; • Organisational changes, such as takeovers, mergers, the sites at which pharmacovigilance is conducted or the delegation/transfer of pharmacovigilance system master file management. In addition to these changes being documented in the pharmacovigilance system master file for the purpose of change control (in the logbook), the QPPV should always been kept informed of these changes. Changes to the pharmacovigilance system master file should be recorded, such that a history of changes is available (specifying the date and the nature of the change), changes to the PSMF must be recorded in the logbook described in Article 5(4) of the Commission Implementing Regulation No 520/2012. Descriptive changes to the content of the master file must be recorded in the logbook. Change history for the information contained in the Annexes may be ‘on demand’, in which case the logbook would indicate the date of the revision of PSMF content and/or Annex update(s), the history of changes for Annex content would also be updated. Information that is being regularly updated and is contained in the Annexes, such as product and standard operating procedure lists or compliance figures, may include outputs from controlled systems (such as electronic document management systems or regulatory databases). The superseded versions of such content may be managed outside of the pharmacovigilance system master file content itself, provided that the history of changes is maintained and available to competent authorities and the Agency on request. If the pharmacovigilance system master file has not been requested, or has remained unchanged for a period of time (for example, if the changes in the content of Annexes are managed outside of the pharmacovigilance system master file), it is recommended that a review is conducted periodically. Marketing authorisations holders need to ensure that the obligations concerning the timely provision of the pharmacovigilance system master file can be met. It is also noted that the QPPV must be able to gain access to current and accurate information about the pharmacovigilance system, hence permanent access to the pharmacovigilance system master file must be enabled, including the information contained in the Annexes (either via the pharmacovigilance master file itself or via access to the systems used to generate the Annex content). Marketing authorisation holders should be able to justify their approach and have document control procedures in place to govern the maintenance of the pharmacovigilance system master file. As a basis for audit and inspections, the pharmacovigilance system master file provides a description of the pharmacovigilance system at the current time, but the functioning and scope of the pharmacovigilance system in the past may need to be understood. Changes to the pharmacovigilance system master file should also account for shared pharmacovigilance systems and delegated activities. A record of the date and nature of notifications of the changes made available to the competent authorities, the QPPV and relevant third parties should be kept in order to ensure that change control is fully implemented. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 15/20 The pharmacovigilance system master file should be retained in a manner that ensures its legibility and accessibility [IR Art 5 and Art 7]. II.B.6. Pharmacovigilance system master file presentation The pharmacovigilance system master file shall be continuously accessible to the QPPV [IR Art 7(2)] and to the competent authorities on request [REG Art 16(4), DIR Art 23(4), IR Art 7]. The information shall be succinct, accurate and reflect the current system in place, which means that whatever format is used, it must be possible to keep the information up to date and, when necessary, to revise to take account of experience gained, technical and scientific progress and amendments to the legislative requirements [IR Art 4(1)]. Although provision of the document within 7 days of request by a competent authority is stated in the Article 23(4) of Directive 2001/83/EC, marketing authorisation holders should be aware that immediate access to the pharmacovigilance system master file may also be required by the competent authorities, at the stated pharmacovigilance system master file location or QPPV site (if different). II.B.6.1. Format and layout The pharmacovigilance system master file may be in electronic form on condition that a clearly arranged printed copy can be made available to competent authorities if requested [IR Art 5(3)]. In any format, the pharmacovigilance system master file should be legible, complete, provided in a manner that ensures all documentation is accessible and allow full traceability of changes. Therefore, it may be appropriate to restrict access to the pharmacovigilance system master file in order to ensure appropriate control over the content and to assign specific responsibilities for the management of pharmacovigilance system master file in terms of change control and archiving. The pharmacovigilance system master file should be written in English (unless the marketing authorisation holder only holds approvals in one Member State when it can be written in the EU official language for that territory), indexed in a manner consistent with the headings described in this Module [IR Art 5], and allow easy navigation to the contents. In general, embedded documents are discouraged. The use of electronic book-marking and searchable text is recommended. Documents such as copies of signed statements or agreements should be included as appendices and described in the index. The documents and particulars of the pharmacovigilance system master file shall be presented with the following headings and, if hardcopy, in the order outlined: Cover Page to include: • The unique number assigned by the EV System to the pharmacovigilance system master file when the XEVPRM is processed in the XEVMPD. • The name of the MAH, the MAH of the QPPV responsible for the pharmacovigilance system described (if different), as well as the relevant QPPV third party company name (if applicable). • The name of other concerned MAH(s) (sharing the pharmacovigilance system) • The list of pharmacovigilance system master files for the MAH (concerning products with a different pharmacovigilance system) • The date of preparation / last update The headings used in II.B.4 should be used for the main content of the pharmacovigilance system master file. The minimum required content of the Annexes is outlined in II.B.4.8, and additional information may be included in the Annexes, provided that the requirements for the content of the Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 16/20 main sections (II.B.1-7) are also met. The positioning of content in the Annexes is further outlined; the bulleted points are descriptions of possible content (and not required headings): The Qualified Person responsible for pharmacovigilance, Annex A • The list of tasks that have been delegated by the QPPV, or the applicable procedural document • The curriculum vitae of the QPPV and associated documents • Contact details supplementary to those contained in XEVMPD, if appropriate The Organisational Structure of the MAH, Annex B • The lists of contracts and agreements Sources of safety data, Annex C • Lists associated with the description of sources of safety data e.g. affiliates and third party contacts Computerised systems and Databases, Annex D Pharmacovigilance Process, and written procedures, Annex E • Lists of procedural documents Pharmacovigilance System Performance, Annex F • Lists of performance indicators • Current results of performance assessment in relation to the indicators Quality System, Annex G • Audit schedules • List of audits conducted and completed Products, Annex H • List(s) of products covered by the pharmacovigilance system • Any notes concerning the MAH per product Document and Record Control, Annex I • Logbook • Documentation of history of changes for Annex contents, indexed according to the Annexes A-H and their content if not provided within the relevant annex itself Documentation to support notifications and signatures concerning the pharmacovigilance system master file, as required. Where there is no content for an Annex, there is no need to provide blank content pages with headings, however, the Annexes that are provided should still be named according to the format described. For example, Annex E should not be renamed to Annex D in circumstances where no Annex concerning computerised systems and databases is used, Annex D should simply be described as ‘unused’ in the indexing, in order that recipients of the pharmacovigilance system master file are assured that missing content is intended. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 17/20 II.C. Operation of the EU network II.C.1. Responsibilities II.C.1.1. Marketing authorisation holders and applicants Marketing authorisation holders shall have a pharmacovigilance system in place to ensure the monitoring and supervision of one or more medicinal products. They are also responsible for introducing and maintaining a pharmacovigilance system master file that records the pharmacovigilance system in place with regard to one or more authorised products [DIR Art 23(4), Art 104(3)(b), REG Art 16(4)]. In accordance with Articles 8 and 104 of the Directive 2001/83/EC a single QPPV shall be appointed to be responsible for the establishment and maintenance of the pharmacovigilance system described in the pharmacovigilance system master file. Applicants are required, at the time of initial marketing authorisation application, to have in place a description of the pharmacovigilance system that records the system that will be in place and functioning at the time of grant of the marketing authorisation and placing of the product on the market. During the evaluation of a marketing authorisation application the applicant may be requested to provide a copy of the pharmacovigilance system master file for review. The applicant/marketing authorisation holder is responsible for establishing the pharmacovigilance system master file in an EU country (at any marketing authorisation holder or contractual partner site including the site of a contractor or marketing partner) and for registering the master file location with the competent authorities in the marketing authorisation application (as applicable) and in the XEVMPD. The pharmacovigilance system master file shall describe the pharmacovigilance system in place at the current time. Information about elements of the system to be implemented in future may be included, but these should be clearly described as planned rather than established or current. The pharmacovigilance system master file creation, maintenance in a current and accessible state (permanently available for audit and inspection purposes) and provision to competent authorities can be outsourced to a third party, but the marketing authorisation holder retains ultimate responsibility for compliance with the legal requirements. When the QPPV and related contact details change or when the location of the pharmacovigilance system master file changes, the marketing authorisation holder is required to submit the appropriate variation application(s) to the national competent authorities or the Agency, as applicable. Marketing authorisation holders will also be responsible for notifying the Agency immediately of any change in the QPPV details and the pharmacovigilance system master file address details so that the Eudravigilance database referred to in Article 24(1) of Regulation (EC) No 726/2004 and when necessary, the European medicines web-portal, are updated accordingly by the Agency [IR Art 4(4)]. II.C.1.2. National competent authorities The national competent authorities are obliged to supervise the pharmacovigilance systems of marketing authorisation holders [DIR Recital 7]. As part of this requirement, they will review the summary information about the pharmacovigilance system included in the marketing authorisation application. The full pharmacovigilance system master file may be requested at any time, for example, to review the description of a pharmacovigilance system of an applicant that has not previously held a marketing authorisation in the EU or where specific concerns about the pharmacovigilance system and/or the product safety profile exist, and in preparation for an inspection (see Module III). Information concerning changes to the summary information or content of the pharmacovigilance system master file will also be used to inform inspection planning and conduct. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 18/20 For centrally authorised products, the Member State where the master file is located will become the supervisory authority [REG Recital 22, Art 18(3)]. For pharmacovigilance systems that include centrally authorised products, as well as nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, national competent authorities will supervise the pharmacovigilance system in co-operation with the supervisory authority and the Agency. For pharmacovigilance systems that do not include centrally authorised products, individual national competent authorities remain responsible for supervision of the pharmacovigilance system and will work together to minimise duplication of effort. National competent authorities will share information about pharmacovigilance systems and use the information to inform national risk-based inspection programmes. Inspectors from national competent authorities will report non-compliance with the requirements of legislation and guidance, including both non-compliance with the requirements for the pharmacovigilance system master file and the pharmacovigilance system (see Module III). II.C.1.3. The European Medicines Agency For centrally authorised products, the Agency co-ordinates the inspections of marketing authorisation holders or their service providers. Supervision of the pharmacovigilance system is based on the location of the pharmacovigilance system master file, with the Member State where the master file is held becoming the supervisory authority [REG Art 18(3)]. The Agency may request the pharmacovigilance system master file in order to fulfil its co-ordination role. The main responsibility of the Agency, in relation to pharmacovigilance system master files, is the maintenance of EU wide databases, dissemination of information and coordination of EU wide activities. To this effect, the Agency, in collaboration with the Member States and the European Commission, is responsible for the set up and maintenance of the European medicines web-portal for the dissemination of information on medicinal products authorised in the EU [REG Art 26]. The Agency will manage the product list described in Article 57 of Regulation (EC) No 726/2004 which provides a practical mechanism for maintaining up-to-date information about the location of the pharmacovigilance system master file, the QPPV contact information and the products relevant to the pharmacovigilance system described in the pharmacovigilance system master file. The list of the locations in the EU where pharmacovigilance system master files are kept will be made public via the web-portal [REG Art 26(1)(e)]. II.C.2. Accessibility of the pharmacovigilance system master file The pharmacovigilance system master file shall be maintained in a current state and be permanently available to the QPPV [IR Art 4(1) and Art7(2)]. It shall also be permanently available for inspection, at the site where it is kept (the stated location), irrespective of whether the inspection has been notified in advance or is unannounced [IR Art 7(3)]. According to Article 104 (3)(b) of the Directive the marketing authorisation holder shall maintain and make available on request a copy of the pharmacovigilance system master file. The marketing authorisation holder must submit the copy 7 days at the latest after receipt of the request from a national competent authority or the Agency. The pharmacovigilance system master file should be submitted in a readable electronic format or clearly arranged printed copy. In the situation where the same pharmacovigilance system master file is used by more than one marketing authorisation holder (where a common pharmacovigilance system is used) the concerned pharmacovigilance system master file should be accessible to each, as any of the applicable marketing Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 19/20 authorisation holders shall be able to provide the file to the competent authorities within 7 days, upon request [DIR Art 23(4), IR Art 7(4)]. The pharmacovigilance system master file should not routinely be requested during the assessment of new marketing authorisation applications (i.e. pre-authorisation), but may be requested on an ad hoc basis, particularly if a new pharmacovigilance system is being implemented, or if product specific safety concerns or issues with compliance with pharmacovigilance requirements have been identified. II.C.3. Transparency Information on the pharmacovigilance system master file location should be made available to the public via the Agency web-portal [REG Art 26] for transparency and communication purposes. Guideline on good pharmacovigilance practices (GVP) – Module II (Rev 1) EMA/816573/2011 Rev I Page 20/20 II.A. Introduction II.B. Structures and processes II.B.1. Objectives II.B.2. Registration and maintenance II.B.2.1. Summary of the applicant’s pharmacovigilance system II.B.2.2. Location II.B.2.3. Registration II.B.2.4. Transfers of responsibilities for the pharmacovigilance system master file II.B.3. The representation of pharmacovigilance systems II.B.4. Information to be contained in the pharmacovigilance system master file II.B.4.1. PSMF section on qualified person responsible for pharmacovigilance (QPPV) II.B.4.2. PSMF section on the organisational structure of the marketing authorisation holder II.B.4.3. PSMF section on the sources of safety data II.B.4.4. PSMF section on computerised systems and databases II.B.4.5. PSMF section on pharmacovigilance processes II.B.4.6. PSMF section on pharmacovigilance system performance II.B.4.7. PSMF section on quality system II.B.4.8. Annex to the PSMF II.B.5 Change control, logbook, versions and archiving II.B.6. Pharmacovigilance system master file presentation II.B.6.1. Format and layout II.C. Operation of the EU network II.C.1. Responsibilities II.C.1.1. Marketing authorisation holders and applicants II.C.1.2. National competent authorities II.C.1.3. The European Medicines Agency II.C.2. Accessibility of the pharmacovigilance system master file II.C.3. Transparency