Pharmastrategie 2026: Arzneimittelversorgung sichern, Innovation stärken, Standort fördern Wie kann Deutschland wichtiger europäischer Pharmastandort bleiben und die Arzneimittelversorgung langfristig sichern? Pharma Deutschland zeigt in fünf Handlungsfeldern, warum eine Pharmastrategie notwendig ist: wettbewerbsfähige Standortbedingungen, resiliente Lieferketten, weniger Bürokratie, mehr Forschung und Innovation sowie eine gestärkte Prävention, Selbstmedikation und Versorgungssicherheit. Mit konkreten Handlungsempfehlungen für Politik, Stakeholder und Öffentlichkeit. Team of pharmacist working on drug discovery.Development of new vaccine.Sterile cleanroom.Antivirus antidote immunization concept.Lab pre-clinic experiment.Disease biochemical analyisis.Diagnostics Inhaltsverzeichnis Deutschland ist als starker Pharmastandort unter Druck Zukunft der Arzneimittelversorgung: Warum Deutschland eine kohärente Pharmastrategie braucht Deutschland als attraktiven Pharmastandort stärken Beispiel EU-Kommunalabwasserrichtlinie (KARL): Fehlende Ressortabstimmung und -koordination belasten Arzneimittelversorgung und Pharmastandort Arzneimittelversorgung langfristig sichern Beispiel Sandoz-Werk in Kundl (Österreich): Mit gezielten Investitionen Versorgungsresilienz in Europa stärken Verfahren beschleunigen und Bürokratie abbauen Beispiel: § 72 AMG Absatz 1 Satz 2 des deutschen Arzneimittelgesetzes hemmt deutsche Pharmaunternehmen im europäischen Wettbewerb Innovation und Forschung fördern Beispiel “Besondere Therapiesituationen”: Reformbedarf bei der Nutzenbewertung innovativer Arzneimittel Prävention und Selbstmedikation stärken Beispiel “Disease Interception” Ansatz: Prävention braucht Paradigmenwechsel Deutschland ist als starker Pharmastandort unter Druck Mit seinem Strategiepapier „Arzneimittelversorgung sichern. Innovation stärken. Standort fördern" legt Pharma Deutschland konkrete Lösungsansätze für eine zukunftsfähige strukturelle Arzneimittelreform vor – entlang von fünf Handlungsfeldern: Pharmastandort, Versorgungssicherheit, Bürokratieabbau, Innovations- und Forschungsförderung sowie Prävention und Selbstmedikation. Zukunft der Arzneimittelversorgung: Warum Deutschland eine kohärente Pharmastrategie braucht Deutschland ist Pharmaland, mit weltweit bekannten Unternehmen, breiter industrieller Basis, mittelstandsgeprägt und hoher Versorgungskompetenz. Doch diese Stärke ist kein Selbstläufer. Wer Versorgung sichern, Arbeitsplätze erhalten und Innovation ermöglichen will, muss die pharmazeutische Industrie als strategische Schlüsselbranche stärken. Im Pharma- und Medizintechnikdialog werden gemäß dem Bundesministerium für Gesundheit (BMG) verschiedene Handlungsfelder diskutiert und Ziele für eine nationale Pharma- und Medizintechnikstrategie abgeleitet werden. Eine übergreifende, kohärente Strategie, die die Themenfelder verbindet und in einen gemeinsamen politischen Handlungsrahmen überführt, steht bislang aber aus. Umso wichtiger ist es, den Dialog zu einem echten konstruktiven Austausch weiterzuentwickeln. Notwendig ist neben der vertieften Diskussion der einzelnen Handlungsfelder vor allem eine koordinierte Gesamtstrategie, die sektorale Perspektiven überwindet, Zielkonflikte transparent adressiert und gemeinsame Lösungen für die Zukunft der Arzneimittelversorgung und des Pharmastandorts entwickelt. Um die Ziele des Pharma- und Medizintechnikdialogs zu erreichen, beschreibt Pharma Deutschland, welche Inhalte eine strukturelle zukunftsfähige Arzneimittelreform haben muss und wie der Spagat aus Finanzierbarkeit von Arzneimitteln, Patientenversorgung, Standortattraktivität und einem relevanten Beitrag zum Wirtschaftswachstum durch die pharmazeutische Industrie zukünftig gelingen kann. Und es kann nur ein Anfang sein. Eine nachhaltig erfolgreiche Strategie muss ressortübergreifend und konsistent erarbeitet und umgesetzt werden, im Dialog mit allen Beteiligten. Für diesen Dialog steht Pharma Deutschland bereit. Der internationale Wettbewerb um Forschung, Produktion und Wertschöpfung verschärft sich. Die USA investieren massiv, China hat Europa bereits 2023 als Hersteller neuer Wirkstoffe überholt. Gleichzeitig bleibt Europa bei Wirkstoffen und deren Vorprodukten verwundbar durch geostrategische Abhängigkeiten. Die Engpässe bei Kinderarzneimitteln und Antibiotika im Herbst und Winter 2022 waren ein Warnsignal. Ohne entschlossenes politisches Handeln drohen Standortverluste, Abhängigkeiten und Versorgungsrisiken. Versorgungssicherheit und Resilienz brauchen Rahmenbedingungen, die wirtschaftliche Tragfähigkeit ermöglichen. Die Versorgung mit essenziellen Arzneimitteln ist nicht allein ein gesundheitspolitisches Thema, sondern Teil der wirtschaftlichen, sicherheitspolitischen und strategischen Resilienz Deutschlands und Europas. Gesundheitsversorgung muss daher stärker als kritische Infrastruktur verstanden und entsprechend priorisiert werden. Generika und Biosimilars stützen die Versorgung in der Breite. Wer sie schwächt, gefährdet Lieferketten, Produktionskapazitäten und industrielle Kompetenz. Auch gehören Forschung und Produktion zusammen. Denn dort, wo Wirkstoffe entwickelt werden, entstehen Know-how, Investitionen und spezialisierte Kapazitäten. Innovationen von heute entscheiden über Versorgung, Wohlstand und strategische Unabhängigkeit von morgen. Doch Investition braucht Verlässlichkeit. Kurzfristige Kostendämpfung, zunehmende Komplexität der Regulierung und unsichere Marktzugänge stehen dazu im Widerspruch. Wer Investitionen in Deutschland will, muss stabile Rahmenbedingungen über Wahlperioden und Ressortgrenzen hinweg sichern, um Patientinnen und Patienten Versorgungssicherheit auf dem aktuellen Stand des medizinischen Fortschritts zu ermöglichen. Das gilt auch auf europäischer Ebene. Eine Strukturreform muss Antworten auf wachsende finanzielle Herausforderungen im Gesundheitswesen geben, die maßgeblich durch den demografischen Wandel geprägt sind. Im Spannungsfeld einer alternden Bevölkerung, steigender Nachfrage und wachsender Ausgaben bei zugleich sinkender Einnahmebasis bedarf es tragfähiger struktureller Lösungen. Dabei kommt dem Heben von Effizienzen sowie der Prävention und der heilberuflich unterstützten Selbstmedikation eine herausragende Bedeutung zu. Sie können entscheidend dazu beitragen, demografisch bedingte Mehrbelastungen langfristig zu begrenzen. Denn angesichts begrenzter Ressourcen darf sich die Reformdebatte nicht allein auf Ausgaben konzentrieren. Ebenso notwendig sind die konsequente Identifikation und Beseitigung von Ineffizienzen im System und eine angemessene Steuerung der Versorgung im Sinne einer bedarfsgerechten und nachhaltigen Patientenversorgung. Zudem darf Investition in eine stabile und resiliente Arzneimittelversorgung nicht ausschließlich als Kostenfaktor, sondern muss als Investition in Versorgungssicherheit, Resilienz und wirtschaftliche Entwicklung verstanden werden. Arzneimittelpolitik braucht einen gemeinsamen politischen Kompass, der Investitionen und Innovation ermöglicht, Versorgung absichert und den Standort stärkt. Dafür müssen Wirtschafts-, Gesundheits-, Forschungs- und Sicherheitspolitik verbindlich zusammenwirken und Arzneimittelpolitik als gemeinsames Politikfeld etabliert werden. Deutschland als attraktiven Pharmastandort stärken Versorgungssicherheit und Resilienz stärken, um Deutschland in geopolitischen Krisen handlungsfähiger und unabhängiger aufzustellen Der Pharmastandort Deutschland zeichnet sich durch seine hohe Leistungsfähigkeit, eine tiefe regionale Verankerung und Vielfalt aus. In Forschung, Entwicklung und Produktion tragen Unternehmen maßgeblich zu Versorgung, Innovation und wirtschaftlicher Wertschöpfung bei. Die Branche sichert die Arzneimittelversorgung, treibt Innovationen voran, schafft zugleich qualifizierte Arbeitsplätze und ist Wirtschaftsmotor. Die Stärkung des Pharmastandortes kann nur durch ein ressortübergreifendes Vorgehen gelingen. Der internationale Wettbewerb um Investitionen in die pharmazeutische Industrie nimmt deutlich zu und stellt den Standort Deutschland zunehmend unter Druck. Bleiben Investitionen aus, gefährdet dies langfristig Wertschöpfung, Versorgungssicherheit und Resilienz. Vor allem die USA nutzen ihre Marktgröße, steuerliche Anreize und regulatorische Erleichterungen, um Investitionen anzuziehen. Gleichzeitig erhöhen Länder wie China mit klarer industriepolitischer Strategie, umfangreichen Subventionen und technologischen Kompetenzen ihre Attraktivität für Forschungs-, Produktions- und Entwicklungsaktivitäten. Daraus ergeben sich für Deutschland und Europa wachsende Standortnachteile. Ursachen sind unter anderem die Fragmentierung des europäischen Marktes, komplexe regulatorische Verfahren, vergleichsweise hohe Steuerbelastungen und Energiepreise. Hinzu kommen ein wenig entwickelter Kapitalmarkt sowie ein zunehmender Fachkräftemangel und gleichzeitiges Abwandern von wichtigem Knowhow. Diese Faktoren sind entscheidend für Investitionsentscheidungen und beeinflussen maßgeblich, wo Innovation künftig entsteht. Versorgungssicherheit und Resilienz sind insbesondere mit Blick auf die geopolitische Lage und mögliche Krisensituationen wichtige Pfeiler für die Aufrechterhaltung der Arzneimittelversorgung in Ausnahmesituationen und im kritischen Umfeld. Gerade hier gilt es, Deutschland sicher aufzustellen und souveräner zu machen. Ziele: Investitionen, Produktion und Forschung in Deutschland halten und ausbauen Schwerpunkte: Wettbewerbsfähige Standortbedingungen schaffen Produktions- und Forschungsinvestitionen fördern Planungssicherheit für Unternehmen erhöhen Europäische Zusammenarbeit gezielt stärken Krisenresilienz schaffen Was jetzt zu tun ist: Arzneimittelpolitik als ressortübergreifendes Politikfeld etablieren , in dem Gesundheits-, Wirtschafts-, Forschungs-, Umwelt- Sicherheits- und Beschäftigungspolitik systematisch aufeinander abgestimmt werden. Ganzheitliche Pharmastrategie entwickeln . Für einen wettbewerbsfähigen und resilienten Pharmastandort braucht es keine isolierten Einzelmaßnahmen, sondern eine unter Einbindung der Pharmaindustrie integrierte, koordinierte Gesamtstrategie. Einzelmaßnahmen in den jeweiligen Handlungsfeldern im Pharmadialog, aber auch in anderen Sektoren, müssen auf die Ziele dieser Gesamtstrategie einzahlen. Globale Standort- und Marktentwicklungen müssen systematisch erfasst, beobachtet und ihre Auswirkungen auf Versorgung und Standort proaktiv adressiert werden . Globale Markt- und Standortentwicklungen müssen kontinuierlich beobachtet, ihre Folgen für Versorgung und Wertschöpfung anerkannt und gemeinsam mit allen Akteuren in angemessene Lösungsstrategien überführt werden. Internationale Entwicklungen, wie die US-Zollpolitik und die Most-Favored-Nation (MFN) Politik, müssen im gemeinsamen Austausch bewertet werden, um Versorgungssicherheit, Wettbewerbsfähigkeit und strategische Souveränität zu stärken. Beispiele liefern Länder wie Großbritannien und dessen Pharmadeal mit den USA, bei welchem Zollfreiheit gegen eine Erhöhung der Arzneimittelausgaben im staatlichen Gesundheitsdienst (National Health Service (NHS)) gewährt wird. Regulierung außerhalb des Gesundheitssektors sowohl auf nationaler als auch auf EU-Ebene stets auf Kollateraleffekte prüfen. Zum Beispiel bei Umweltauflagen auf EU-Ebene darauf hinwirken, dass Umweltziele nicht durch einseitige Kostenverteilung zulasten der Wettbewerbsfähigkeit erreicht werden. Die vorgeschriebene Folgenabschätzung (Impact Assessment) vor europäischen Regelungsvorschlägen durchführen. Dieses wird derzeit nicht konsequent für alle Regelungsvorhaben auf EU-Ebene umgesetzt. Langfristige, stabile und verlässliche Rahmenbedingungen für Investitions- und Standortentscheidungen brauchen Kontinuität. Sie müssen auch über Wahlperioden hinweg Bestand haben. Deutschland und Europa müssen ihre Standortbedingungen für Pharma-Investitionen verbessern, z. B. durch Bürokratieabbau, schnelle Markteinführungen, innovationsfreundliche Vergütung sowie stärkere steuerliche und finanzielle Anreize für Forschung und Produktion. Denn eine volatile, sich widersprechende Gesetzgebung führt zu fehlender Planbarkeit und ausbleibenden Investitionsentscheidungen. Anreizsysteme ausbauen, die den Pharmastandort Deutschland stärken , z.B. über steuerliche und finanzielle Anreize für Forschung, Produktion und Wertschöpfung. Zum Erhalt und zur Sicherung der internationalen Wettbewerbsfähigkeit bestehender Produktions- und Forschungskapazitäten bedarf es einer gezielten industriepolitischen Strategie sowie passgenauer Förderinstrumente. Beispiel EU-Kommunalabwasserrichtlinie (KARL): Fehlende Ressortabstimmung und -koordination belasten Arzneimittelversorgung und Pharmastandort Umweltreaktionsteam in Hazmat-Anzügen Sammeln von Abwasserproben in der Nähe von Industrie Abwasserentwässerungsrohren Das Beispiel KARL verdeutlicht die Herausforderungen und die Notwendigkeit eines abgestimmten, ressortübergreifenden Handelns, um Zielkonflikte zwischen Politikfeldern sichtbar zu machen und geplante Regelungen entsprechend auszurichten. Gesundheit und Nachhaltigkeit müssen gemeinsam gedacht werden, ohne die Versorgungssicherheit und den Pharmastandort Deutschland zu gefährden. Zielsetzung und Ausgestaltung erfolgen hier jedoch maßgeblich aus einer sektoralen Perspektive, ohne die Wechselwirkungen mit industrie-, forschungs- und standortpolitischen Zielsetzungen hinreichend zu berücksichtigen. Die Richtlinie in ihrer derzeitigen Ausgestaltung birgt die akute Gefahr für Kollateralschäden in der Arzneimittelversorgung, insbesondere bei Generika. In diesem Bereich können Preissteigerungen aufgrund gesetzlicher Vorgaben und der Preisgestaltung nicht über das Erstattungssystem abgefedert werden. Die Last der Herstellerverantwortung wird insbesondere den generischen Sektor finanziell sehr stark treffen, wodurch die Gefahr besteht, dass eine Vielzahl an essenziellen Arzneimitteln nicht mehr kostendeckend hergestellt werden können. Dies widerspricht aber klar dem Ziel der Bundesregierung und der Europäischen Union, die Versorgungssicherheit zu verbessern sowie die Abhängigkeit der Gesundheitssysteme von Drittstaaten zu reduzieren. Das Beispiel zeigt, dass fehlende Koordination zu inkonsistenten Rahmenbedingungen führt, die für Unternehmen schwer kalkulierbar sind. Eine solche Fragmentierung politischer Zuständigkeiten erschwert es, kohärente und langfristig tragfähige Strategien für den Pharmastandort zu entwickeln. KARL steht damit exemplarisch für die Notwendigkeit, Pharmapolitik als integriertes Politikfeld zu verstehen, in dem gesundheitliche, wirtschaftliche und industriepolitische Ziele systematisch zusammengeführt werden. Ohne eine solche Abstimmung besteht die Gefahr, dass Einzelmaßnahmen ihre beabsichtigte Wirkung verfehlen oder kontraproduktive Effekte für Versorgung und Standort entfalten. Arzneimittelversorgung langfristig sichern Ein automatisiertes System mit Roboterarm entnimmt Medikamente aus einem Lagerregal in der Kaufpark Apotheke in Ahrensfelde. Viele Apotheken setzen inzwischen auf digitale Technik und Automatisierung, um Arbeitsabläufe zu beschleunigen und die Arzneimittelversorgung effizient zu organisieren. Lieferketten widerstandsfähiger machen, europäische Eigenständigkeit stärken und kritische Arzneimittel gezielt absichern Eine resiliente und krisenfeste Arzneimittelversorgung entsteht nicht kurzfristig, sondern muss langfristig aufgebaut werden. Generika und Biosimilars spielen dabei eine zentrale Rolle für die Stärkung der Versorgungssicherheit, die Resilienz des Gesundheitssystems und die strategische Autonomie. Eine wirtschaftlich tragfähige Produktion ist notwendig, um industrielle Fähigkeiten, stabile Lieferketten und bestehende Infrastrukturen im Normalbetrieb zu sichern und im Krisenfall schnell ausweiten zu können. Die Entwicklungen der vergangenen Jahre verdeutlichen die hohe Verwundbarkeit der Lieferketten für generische Arzneimittel. Die starke Abhängigkeit Europas von außereuropäischen Produktionsstandorten, insbesondere in China, stellt dabei ein erhebliches wirtschafts- und sicherheitspolitisches Risiko dar. Um die Versorgungssicherheit nachhaltig zu stärken, sind Deutschland und Europa gefordert, ihre Eigenständigkeit in der Arzneimittelversorgung zu stärken. Erstattungsregelungen müssen so ausgestaltet werden, dass steigende Produktionskosten und regulatorische Anforderungen angemessen berücksichtigt werden. Zugleich gilt es zu vermeiden, Fehlentwicklungen aus der Generikaversorgung auf den patentgeschützten Markt zu übertragen. Insbesondere dürfen keine zusätzlichen Rabattmechanismen eingeführt werden, die im Generikamarkt bereits zu Versorgungsproblemen, wirtschaftlichem Druck und einer verminderten Resilienz der Lieferketten geführt haben. Vielmehr muss der Critical Medicines Act der Europäischen Union genutzt werden, um die Versorgungssicherheit bei kritischen Arzneimitteln zu stärken. Seine Instrumente müssen konsequent auf tatsächlich kritische Arzneimittel fokussiert und mit resilienten Beschaffungs- und Produktionsmechanismen verknüpft werden. Ziel: Verlässliche Versorgung mit Generika, Biosimilars und innovativen Arzneimitteln und damit therapeutische Vielfalt gewährleisten. Schwerpunkte: Lieferketten widerstandsfähiger machen Kritische Produktionskapazitäten in Europa stärken bzw. erhalten Marktaustritte bei Generika/Biosimilars und Innovationen (chemische, bio- und gentechnologische, phytotherapeutische) verhindern Frühzeitigen Zugang zu Innovationen für Patientinnen und Patienten sicherstellen Was jetzt zu tun ist: Die wirtschaftlichen Rahmenbedingungen für Generika müssen, angepasst an die Versorgungskritikalität, reformiert werden. Insbesondere durch Abschaffung des Preismoratoriums sowie eine Reform des Festbetrags- und Rabattvertragssystems, da die derzeitigen Preise eine kostendeckende Produktion kaum ermöglichen. Möglichkeiten ausbauen, im Bedarfsfall Instrumente wie Festbeträge oder Rabattverträge gezielt und befristet außer Kraft zu setzen, um kurzfristige Maßnahmen zur Sicherstellung der Versorgung umsetzen zu können. Anreize und Refinanzierungsmodelle für Unternehmen schaffen, Kapazitäten für versorgungskritische Arzneimittel vorzuhalten und im Krisenfall kurzfristig auszuweiten , z.B. gemeinsame Entwicklung und Umsetzung eines Resilienzmodells für wichtige Arzneimittel, Risiken breiter verteilen und gezielt Anreize schaffen, damit Unternehmen Reservekapazitäten aufbauen und im Markt bleiben. Als Beispiel kann hier das „Hot-Spare-Capacity-Modell“ für die Pharmaproduktion in Sachsen-Anhalt dienen. Grundprinzip ist, dass sich Land und Unternehmen gemeinsam für eine Förderung von Rüst- und Vorhaltekosten einsetzen, die ein schnelle Kapazitätsskalierung für den Krisenfall ermöglichen. Unternehmen erklären ihre Bereitschaft, ihre Produktionskapazitäten innerhalb einer festgelegten Frist hochfahren zu können, eine Prämie bemisst sich an den Kosten für diese Flexibilität. Angestrebt ist eine Ko-Finanzierung aus Landes-, Bundes- oder EU-Mitteln. Produktoptionen für einen Ausbau der Selbstmedikation erweitern , vor allem durch Verbesserung des sog. Switch-Verfahrens sowie der Marktzugangsvoraussetzungen für Phytotherapeutika (Vgl. Kapitel 5). Verantwortung für Versorgungssicherheit und Krisenresilienz als gesamtgesellschaftliche Aufgabe anerkennen, mit entsprechenden Ko-Finanzierungsansätzen. Die Sicherstellung der Versorgung mit versorgungskritischen Arzneimitteln ist gemeinsame Aufgabe, die auch gemeinsam mit Hilfe öffentlicher Mittel finanziert werden muss. Denn Versorgungssicherheit und Krisenresilienz sind nicht alleinige Aufgabe von Unternehmen, sondern ebenso Daseinsfürsorge und von hoher Relevanz für sicherheitspolitische Zielsetzungen. Generika und Biosimilars wirtschaftlich tragfähig absichern , damit Produktionskompetenz, Lieferketten und industrielle Infrastruktur erhalten bleiben und Marktaustritte verhindert werden. Neue Vergütungsmodelle wie das „Netflix-Modell“ für wichtige Arzneimittel wie Antibiotika strukturell ermöglichen. Bei einem solchen „Abo“-Modell würden die Kosten für die Arzneimittel abgekoppelt von der Anzahl der Patienten und der Anzahl der verkauften Packungen. Es eignet sich insbesondere für Arzneimittel mit begrenztem Absatzpotenzial und zugleich hoher Versorgungsrelevanz, wie beispielsweise Reserveantibiotika. Herstellern wäre hiermit eine jährliche Bezahlung garantiert, die vom Verkaufsvolumen losgelöst ist. Mit der Umsetzung solcher innovativer Finanzierungsmodelle könnten Investitionen in Forschung, Entwicklung und Produktion in Deutschland wirtschaftlich tragfähig gemacht werden, Versorgungssicherheit gestärkt werden. Nationale Produktionskapazitäten für versorgungskritische Arzneimittel, Wirkstoffe und Vorprodukte systematisch erfassen, beobachten und bewerten, um so unter Einbezug aller relevanten Stakeholder geeignete Handlungsschritte ableiten zu können . Struktureller Ansatzpunkt für ein solches Monitoring könnte beispielsweise das im Zuge des Arzneimittel-Lieferengpassbekämpfungs- und Versorgungsverbesserungsgesetz (ALBVVG) am Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) angegliederte Frühwarnsystem für Arzneimittellieferengpässe bieten. Wichtig ist, dass vorhandene Daten genutzt werden, damit keine zusätzlichen Meldungen oder Informationspflichten entstehen, die Unternehmen belasten und Bürokratie schaffen. Ausschreibungen und Rabattverträge systematisch danach ausrichten, dass Versorgungssicherheit gestärkt wird. Dabei kein einseitiger Fokus auf Preis als Kriterium. Modelle nutzen, die mehrere Anbieter am Markt halten und den Markt breit halten, statt ihn zu verengen. Hierzu gehören ein Verbot exklusiver Rabattverträge für versorgungskritische Arzneimittel und eine verbindliche Einführung von Vergabekriterien (Most Economically Advantageous Tender, MEAT), die Produktionsstandort bzw. Lieferkettendiversifizierung und -resilienz würdigen. Markteintritts- und Produktionshürden abbauen , z.B. Vorgaben wie starre Vorratspflichten flexibilisieren und regulatorische Anforderungen so gestalten, dass zusätzliche Anbieter in den Markt kommen. Ausschließliche elektronische Packungsbeilage. Dies vereinfacht Produktion und, erleichtert die Umverteilung von Waren über Länder hinweg. Beispiel Sandoz-Werk in Kundl (Österreich): Mit gezielten Investitionen Versorgungsresilienz in Europa stärken ABD0075_20231110 - KUNDL - ÖSTERREICH: Außenansicht des Gebäudes einer neuen Produktionsanlage zur Herstellung von Penicillin-Wirkstoffen des Schweizer Generika-Herstellers Sandoz, aufgenommen am Freitag, 10. November 2023, in Kundl. - FOTO: APA/MARKUS STEGMAYR - 20231110_PD4234 Ein konkretes Beispiel für den gezielten Ausbau von Versorgungsresilienz ist die Förderung des Sandoz-Standorts in Kundl (Österreich). Das Werk ist eines der letzten verbliebenen Produktionszentren für Penicillin-Antibiotika in Europa und deckt als integrierter Standort die gesamte Wertschöpfungskette – vom Wirkstoff bis zur fertigen Darreichungsform – ab. Vor dem Hintergrund zunehmender Abhängigkeiten von außereuropäischen Produktionsstandorten hat die österreichische Bundesregierung gemeinsam mit der Europäischen Kommission gezielt in die Sicherung und Modernisierung dieser kritischen Infrastruktur investiert. Im Rahmen eines genehmigten Beihilfeverfahrens erhielt Sandoz einen nicht rückzahlbaren Zuschuss in Höhe von rund 28,8 Mio. Euro, ergänzt um weitere nationale Fördermittel. Ziel war es, die Produktion technologisch zu modernisieren, nachhaltiger zu gestalten und langfristig am Standort zu sichern. Die Gesamtinvestitionen beliefen sich dabei auf rund 150 Mio. Euro, wovon ein Großteil durch das Unternehmen selbst getragen wurde. Neben dem Direktzuschuss gewährte Österreich Sandoz auch Beihilfen i. H. v. etwa € 10-15 Mio. aus bestehenden nationalen Förderprogrammen. Das Beispiel zeigt, dass die gezielte öffentliche Unterstützung strategisch relevanter Produktionskapazitäten dazu beitragen kann, industrielle Kernkompetenzen in Europa zu erhalten und gleichzeitig Anreize für private Investitionen zu setzen. Entscheidend ist dabei die Einbettung in eine kohärente industriepolitische Strategie, die Versorgungssicherheit, Innovationsfähigkeit und Wettbewerbsfähigkeit gemeinsam adressiert. Insbesondere bei generischen Arzneimitteln stehen wirtschaftlich nicht tragfähige Rahmenbedingungen häufig im Widerspruch zu dem Ziel, Produktionskapazitäten im Inland oder in Europa zu sichern bzw. auszubauen. Das Beispiel Kundl verdeutlicht damit, dass Versorgungsresilienz nicht allein durch regulatorische Maßnahmen erreicht werden kann, sondern eine aktive industriepolitische Flankierung erfordert. Verfahren beschleunigen und Bürokratie abbauen Microbiologist examining cells on device screen in laboratory || Modellfreigabe vorhanden Verfahren beschleunigen, Bürokratie abbauen und Innovationen schneller in die Versorgung bringen Komplexe und langwierige Verfahren stehen einer Förderung von Standort und Innovation klar entgegen. Die bürokratischen Belastungen für Unternehmen sind hoch, was Planungsprozesse verlängert und immense Ressourcen bindet. Deutschland verfügt über eine starke Grundlagenforschung, verliert jedoch an Wettbewerbsfähigkeit bei der Translation, klinischer Entwicklung und industrieller Skalierung. Hemmnisse sind überbordende, teilweise nicht zielgerichtete Bürokratie, fragmentierte Zuständigkeiten und Verfahrensabläufe, Mehrfachregulierung und langwierige, teils intransparente Genehmigungsprozesse unter Beteiligung verschiedener Behörden, welche Innovationsgeschwindigkeit und Investitionen ausbremsen. Vor diesem Hintergrund sind ein konsequenter Abbau von Bürokratie auf allen Ebenen und eine Beschleunigung zentraler Prozesse wesentliche Hebel, um Innovationen schnell in die Versorgung zu bringen und den Standort Deutschland wettbewerbsfähig zu halten. Auch müssen Prozesse der Digitalisierung vorangetrieben werden. Angesichts dynamischer europäischer Vorgaben und globaler Entwicklungen können nationale Digitalisierungsinitiativen mithilfe industrieller Innovationsimpulse ihre Wettbewerbsfähigkeit sichern. Daher bedarf es eines weiterentwickelten Verständnisses der Zusammenarbeit zwischen Politik, Verwaltung und Industrie. Handlungsleitend muss ein Ermöglichen und kein Verhindern sein. Die derzeitigen rechtlichen Rahmenbedingungen führen jedoch dazu, dass die industrielle Gesundheitswirtschaft häufig nur indirekt eingebunden ist. Gleichzeitig werden die Entwicklung und Markteinführung patientennaher Innovationen durch restriktive nationale Vorgaben und überbordende Interpretation des Wirtschaftlichkeitsgebots oftmals ausgebremst. Ziel: Arzneimittel schnell zu Patientinnen und Patienten bringen. Schwerpunkte: Zulassungs- und HTA-Verfahren beschleunigen Doppelprüfungen vermeiden Prozesse digitalisieren Berichtspflichten und Verwaltungsaufwand reduzieren Nationale Vorgaben an Versorgungspraxis orientieren Was jetzt zu tun ist: Genehmigungsverfahren für klinische Studien von Arzneimitteln und Medizinprodukten harmonisieren und beschleunigen. Festzustellen sind unterschiedliche Datenschutzinterpretationen über die einzelnen Bundesländer hinweg. Einzelne schwerfällige oder besonders formelle Ethik-Kommissionen und z.T. lange Vertragsverhandlungen bremsen Studien und klinische Prüfungen oft um Monate aus oder lassen sie nicht mehr in Deutschland stattfinden, weil sie in anderen Ländern schon weit vorangeschritten sind. Empfehlenswert wäre eine Standardisierung der Verfahren der Ethik-Kommissionen mit klaren Fristen, mit eineindeutig beschriebenen Versagungsgründen nach Maßgabe der EU-Verordnung 536/2014, mit vollständig digitalen Antragsprozessen und transparenter, barrierefreier Kommunikation in der Planungsphase für eine klinische Prüfung sowie in der Bewertungsphase eines Antrags auf Durchführung einer klinischen Prüfung. Die Kommunikation muss konsequent nach den Bedürfnissen der Antragsteller sowie am Prüfplan und Studiendesign ausgerichtet werden. Zudem müssen klare gesetzliche Regeln für die Legitimierung der fortgeschrittenen elektronischen Signaturen im Studienkontext, inkl. der informierten Einwilligung und Studienverträge, und eine bindende Vorgabe zur Verwendung der fortgeschrittenen elektronischen Signatur gelten - wie im ursprünglichen Referentenentwurf des Medizinforschungsgesetzes (MFG) vorgesehen. Europäische Zuständigkeiten klar regeln und Doppelprüfungen vermeiden, bspw. im Zusammenhang der SoHo-Verordnung und deren Überführen/Anwendung in deutsches Recht. Doppelregelungen auch zwischen der ATMP-Verordnung und dem Biotech Act müssen vermieden werden. Hier geht es bspw. um eine zukunftsfähige, flexible AMTP-Definition oder den Umgang mit genetisch veränderten Organismen nach ATMP-Recht und Biotech Act. Doppelregulierung zwischen Arzneimittel- und Gentechnikrecht abbauen: Im Konfliktfeld zwischen ATMP- und Gentechnik-Recht ist zu berücksichtigen, dass das Gentechnikrecht im Gegensatz zum ATMP-Rechtsrahmen auf die Vermeidung von Risiken für die Umwelt fokussiert ist. Anpassungsbedarf sieht Pharma Deutschland u.a. in Bezug auf die Einstufung und die Risikoklassen nach der ATMP-Verordnung sowie in der (uneinheitlichen) Überwachungspraxis. Nationale Regelungen konsequent auf zusätzliche Anforderungen unterhalb des EU-Rechts prüfen und begründungspflichtig machen . Abweichungen werden auf ein Mindestmaß beschränkt, um unnötige Bürokratie zu vermeiden, Verfahren zu vereinfachen und die Wettbewerbsfähigkeit des Standorts Deutschland zu stärken. Wir sehen u.a. sehr uneinheitliche und komplexe nationale Genehmigungsverfahren für notwendige Tierversuche in Deutschland. U.a. auch deshalb sinkt die Zahl der Tierversuche in Deutschland, Unternehmen wandern mit Studien ins Ausland ab. Erfahrungen mit dem EU-HTA und nationalen Nutzenbewertungsverfahren systematisch evaluieren und kontinuierlich so weiterentwickeln, dass Bürokratie abgebaut und nicht vermehrt wird. Keine vierte Hürde für die GKV-Erstattung etablieren, die insbesondere durch die nationale untergesetzliche Normgebung wie Arzneimittel-Richtlinie und Packungsgrößenverordnung bürokratische und versorgungsferne Verwaltungsakte mit sich bringen, welche Selbstverwaltung und Pharmaunternehmen gleichermaßen belasten. Gezielter Ausbau von Dateninfrastrukturen unter Berücksichtigung der Interoperabilität von Systemen auf Basis international etablierter IT - zur sicheren, effizienten und sektorübergreifenden Datennutzung für Forschung, KI und personalisierte Medizin. Aktiver Einbezug der industriellen Gesundheitswirtschaft in der Schaffung eines Gesundheitsdatenökosystems und Datenzugang für Industrie, Wissenschaft und Versorgung gleichberechtigt ermöglichen. KI-Readiness und KI-Real- bzw. regulatorische Labore schaffen. Beispiel: § 72 AMG Absatz 1 Satz 2 des deutschen Arzneimittelgesetzes hemmt deutsche Pharmaunternehmen im europäischen Wettbewerb Ein Mitarbeiter kommissioniert am 29.10.2013 im Zentrallager des Pharma-Großhändlers AEP direkt in Alzenau (Bayern) eine Bestellung. Der neue Anbieter will mit einem Discounter-Modell den Markt aufmischen. Foto: David Ebener/dpa (zu dpa "Mit Discounter-Modell in den Preiskampf des Pharmagroßhandels" vom 06.11.2013) ++ In § 72 AMG „Einfuhrerlaubnis“ fordert das deutsche Arzneimittelgesetz in Absatz 1 Satz 2 von pharmazeutischen Unternehmen eine spezielle Einfuhrerlaubnis für Wirkstoffe aus Drittländern (außerhalb der Europäischen Union), die menschlicher, tierischer oder mikrobieller Herkunft sind oder die auf gentechnischem Wege hergestellt werden (sog. MTMG-Wirkstoffe). Die Anforderung einer Einfuhrerlaubnis für Wirkstoffe menschlicher Herkunft wurde unlängst in der SoHo (Substances of Human origin)-Verordnung Nr. 2024/1938 neu geregelt. Die Regelung zu Wirkstoffen tierischer oder mikrobieller Herkunft sowie solcher, die auf gentechnischem Wege hergestellt wurden, ist hingegen eine deutsche Besonderheit, die sich nicht im europäischen Pharmarecht findet. Gleiches gilt für die geforderte Einfuhrerlaubnis für Arzneimittel aus Drittstaaten und die geforderten zusätzlichen Zertifikate für sog. MTMG-Wirkstoffe. Kein anderer Mitgliedstaat der EU fordert eine solche zusätzliche Einfuhrerlaubnis für Arzneimittel oder MTMG-Wirkstoffe. Die Verpflichtung hinsichtlich der geforderten Zertifikate für die Einfuhr von MTMG-Wirkstoffen führt dazu, dass zusätzliche behördliche Inspektionen in Drittländern, aus denen die genannten Wirkstoffe stammen (vor allem aus China und Indien), notwendig sind, was in Zeiten besonders knapper Ressourcen auf Seiten der zuständigen Behörden sowie Erschwernisse durch das chinesische Antispionagegesetz problematisch ist. Ohne solche Zertifikate ist der Import der genannten Wirkstoffe, zu denen auch Antibiotika zählen (mikrobiologisch hergestellt), nach Deutschland nicht möglich. Das Beispiel zeigt, dass die zusätzlichen Verpflichtungen nach deutschem Recht ein klassisches „Gold-plating“ darstellen und die Unternehmen in Deutschland mehr als ihre Wettbewerber im EU-Ausland belasten. Die Anforderungen aus § 72 Absatz 1 Satz 2 AMG sind weder im EU-Recht gefordert noch sachlich notwendig und müssen daher gestrichen werden. Außerdem muss die Zollbescheinigung gemäß § 73 Abs. 6 AMG abgeschafft werden. Für die zollamtliche Prüfung der importierten Waren sind die arzneimittelrechtlich geforderten Zertifikate gemäß § 73 Abs. 6 AMG unerheblich. Die arzneimittelrechtlichen Anforderungen sind durch die Zulassung, Herstellungserlaubnis inkl. ihrer Anlagen sowie die Eintragung in der einschlägigen Datenbank gewährleistet. Innovation und Forschung fördern Scientist and android AI robot working together in the lab, the robot is examining the samples under a microscope Innovationsoffenheit, Planungssicherheit und moderne Bewertungsverfahren für einen starken Forschungsstandort schaffen Das AMNOG ist seit 2011 ein international anerkanntes Instrument der frühen Nutzenbewertung und nutzenbasierten Preisfindung. Es verbindet einen schnellen Zugang zu innovativen Arzneimitteln mit Einsparungen für die gesetzliche Krankenversicherung. Präzisionsmedizinische Ansätze, tumoragnostische Behandlungen, Arzneimittel für neuartige Therapien (ATMP) und hochspezialisierte Orphan Drugs prägen zunehmend die wissenschaftliche Entwicklung und stellen das System vor neue Herausforderungen. Es muss gezielt weiterentwickelt werden, um Innovationsoffenheit, Versorgungssicherheit und Planungssicherheit auch künftig zu gewährleisten. Deutschland zählt beim Zugang zu innovativen Arzneimitteln bislang zu den europäischen Spitzenreitern. Dieser Standortvorteil gerät jedoch zunehmend unter Druck. Insbesondere die Regelungen des GKV-Beitragssatzstabilisierungsgesetzes mit Zwangsrabatten und Rabattmechanismen im patentgeschützten Markt schwächen die Attraktivität Deutschlands als Innovationsstandort, erhöhen das Risiko von Marktrücknahmen, Beschränken die Therapieentscheidungen behandelnder Ärzte und gefährden langfristig die Therapievielfalt für Patientinnen und Patienten. Eine zukunftsfähige Arzneimittelpolitik muss daher die nutzenbasierte Preisfindung stärken, statt diese zu untergraben. Darüber hinaus ist die Wertschöpfung aus der Weiterentwicklung bekannter Wirkstoffe, dem sogenannten Repurposing, noch nicht erfolgt. Insbesondere versperren hier die vorhandenen Steuerungsinstrumente der GKV-Erstattung die Weiterentwicklung in der Arzneimitteltherapie und damit innovative Neuerung in der Versorgung. So fehlt es zum Beispiel für die Entwicklung von neuen Darreichungsformen oder Erweiterungen für neue Indikationen an einem Return on invest aus dem System. Gerade das Repurposing stellt jedoch eine Chance dar, für das System kostengünstig eine Weiterentwicklung von Arzneimitteltherapien zu erreichen, die sich in der Zukunft gesundheits- und sozialwirtschaftlich auszahlen. Zudem finden Weiterentwicklungen, die sich z. B. auf die umweltfreundlichere Herstellung von Wirkstoffen und Arzneimitteln beziehen, und damit nachhaltig wirken, keine Berücksichtigung hinsichtlich der Refinanzierung im System. Ziel: Deutschland als führenden Standort für pharmazeutische Forschung und Entwicklung etablieren. Schwerpunkte: Klinische Forschung erleichtern Forschungsförderung gezielt ausbauen Datenzugang für Forschung verbessern Anreize für Innovationen schaffen Hürden für Weiterentwicklungen abbauen Was jetzt zu tun ist: Innovationsfreundliche Rahmenbedingungen mit Engagement für schnellere Zulassungspfade, Unterstützung klinischer Studien und bessere Nutzung von Gesundheitsdaten. Hierzu gehört auch eine international wettbewerbsfähige Forschungs- und Innovationsförderung entlang der gesamten Innovationskette. Konkrete Maßnahmen beinhalten insbesondere eine Weiterentwicklung der Forschungszulage, um forschungsintensive Unternehmen noch stärker anzusprechen und bestehende Anwendungshemmnisse abzubauen, die Einführung zusätzlicher Abschreibungsmöglichkeiten für private FuE-Investitionen, ein sektorspezifischer Pharma-Innovationsfonds zur Finanzierung der kapitalintensiven Translations-, Entwicklungs- und Skalierungsphasen sowie eine steuerliche Begünstigung von Erträgen aus geistigem Eigentum, um die wirtschaftliche Verwertung von in Deutschland entwickelten Innovationen zu stärken und Forschung, Entwicklung und Wertschöpfung langfristig am Standort zu halten. Kooperationen zwischen Forschungseinrichtungen und Industrie ausbauen und administrative Hürden reduzieren. Preisbildung für neue Arzneimittel kontinuierlich weiterentwickeln und modernisieren . Beispielsweise durch neue Anreizmodelle in der Preisbildung von Arzneimitteln mit Zusatznutzen, stärkere Nutzung von Pay for Performance Modellen für Innovationen mit begrenzter Evidenzbasis bei Markteintritt, um frühen Zugang und geteilte Risikoübernahme miteinander zu verbinden. Nutzenbasierte Preisfindung im Rahmen flexibler Verhandlungsmöglichkeiten stärken und Weiterentwicklung des AMNOG . Dazu gehört, dass keine starren Preis-Mengen Vorgaben für nutzenbewertete Arzneimittel oder Rabattverträge für patentgeschützte Arzneimittel weiterverfolgt werden. Sie unterlaufen das AMNOG-Verfahren und die nutzenbasierte Preisfindung. Stattdessen muss das AMNOG weiterentwickelt werden. Hierzu zählen die Anerkennung besonderer Therapiesituationen verbunden mit stärkerer Anerkennung von Versorgungsdaten und Real-World-Daten im Rahmen der Nutzenbewertung, mehr Planungssicherheit durch Berücksichtigung der vom Gemeinsamen Bundesausschuss (G-BA) beratenen zweckmäßigen Vergleichstherapie sowie die Anhebung der Freistellungsgrenze in der Nutzenbewertung und eine Ausnahmeregelung für bestimmte Produktgruppen wie Diagnostika und Arzneimittel für Kinder. Die internationale Preisreferenzierung eindämmen , da durch Preisexport von wirtschaftlichen schwächeren Ländern in wirtschaftlich stärkere Länder Unternehmen dazu gezwungen werden, ihre Arzneimittel in Niedrigpreisländern nicht mehr anzubieten. Die Bundesregierung muss sich für die Abschaffung von internationaler Preisreferenzierung stark machen, sodass die Industrie auf Basis eines kaufkraftadjustierten Preises Arzneimittel anbieten kann und damit der Zugang für alle Patienten verbessert wird. Dabei ist zu akzeptieren, dass wirtschaftlich starke Länder einen höheren Anteil an Forschungs- und Entwicklungskosten tragen. Ein Warenimport und -export im europäischen Wirtschaftsraum ist davon nicht betroffen und bleibt erhalten. Auf nationaler Ebene ist ein Ansatzpunkt bereits über vorhandene Regelungen zum vertraulichen Erstattungsbetrag gegeben. In diesem Zusammenhang plädiert Pharma Deutschland für einen Wegfall des 9% Abschlags auf Vertraulichkeit sowie die Abschaffung der Differenz der Apothekenaufschläge zwischen Listenpreis und Erstattungsbetrag. Innovationsfreundlichere Behandlung von Weiterentwicklungen etablierter Wirkstoffe zum Beispiel durch die Schaffung von preislichen Spielräumen bei Repurposing. Unternehmen können generische Arzneimittel weiterentwickeln und so Innovation in die Patientenversorgung zu niedrigen Kosten bringen. Beispiele hierfür sind die Erforschung neuer Indikationen mit alten Wirkstoffen, Darreichungsforminnovationen, Dosierungsanpassungen für vulnerable Gruppen wie Kinder, Schwangere, etc. Die bestehenden Möglichkeiten werden aber nicht umgesetzt, da auf Basis der bestehenden Preisregulierung eine Refinanzierung der Investition nicht möglich ist, z.B. aufgrund der geltenden Festbetragsregelungen, Rabattverträgen im generischen Segment und Preismoratorium, sowie teilweise ein Durchlaufen des Nutzenbewertungsverfahrens bei neuem Unterlagenschutz. Diese Regeln gilt es zu überprüfen und hier Innovation zuzulassen, die für eine bessere Patientenversorgung zu niedrigen Kosten führt. Anreize und Möglichkeiten für ein Return on Investment schaffen. Hinsichtlich der Weiterentwicklung bekannter Wirkstoffe gilt es zudem Anreize für die Investition in Forschung und Entwicklung ebendieser zu schaffen. Dabei muss unbedingt der Fokus weg von der Wirtschaftlichkeit im System Gesundheitswirtschaft hin zu einer ganzheitlichen Betrachtung erfolgen, die auch den sozial-, volkswirtschaftlichen und nachhaltigen Nutzen für die Gesellschaft in die Bewertung mit einbezieht Beispiel “Besondere Therapiesituationen”: Reformbedarf bei der Nutzenbewertung innovativer Arzneimittel Male Neurologist Monitoring Brain Scan On Computer Screen In Clinic. Female Technician Using Radiology Technology Ein zentrales Spannungsfeld betrifft die Anerkennung besonderer Therapiesituationen. § 5 Abs. 3 AM-NutzenV (Arzneimittel-Nutzenbewertungsverordnung) sieht ausdrücklich vor, dass Nachweise der bestverfügbaren Evidenzstufe einzureichen sind, wenn Studien höchster Evidenzstufe unmöglich oder unangemessen sind. Dies betrifft insbesondere seltene Erkrankungen sowie neuartige oder hoch personalisierte Therapieansätze, deren Studiendesign keine klassische Randomisierung zulässt. In der praktischen Umsetzung läuft diese Regelung allerdings ins Leere. Einarmige Studien und externe Kontrollarme mit historischen Vergleichen, indirekte Vergleiche oder adaptive Studiendesigns werden regelhaft als nicht ausreichend für den Nachweis eines Zusatznutzens anerkannt. Gleichzeitig akzeptieren Zulassungsbehörden seit Jahren situationsangemessene Evidenz, insbesondere bei seltenen Erkrankungen, hohem Schweregrad oder ungedecktem medizinischen Bedarf. Diese Divergenz führt zu Inkohärenzen zwischen Zulassung und Nutzenbewertung und kann die Verfügbarkeit innovativer Therapien beeinträchtigen. Erforderlich ist daher ein strukturiertes Verfahren zur frühzeitigen Feststellung besonderer Therapiesituationen sowie die grundsätzliche Reduktion methodischer Hürden im Verfahren. Der Gemeinsame Bundesausschuss (G-BA) muss auf Antrag des pharmazeutischen Unternehmens unter Einbindung von Zulassungsbehörden, wissenschaftlich-medizinischer Fachgesellschaften sowie Behandlungsexpertise transparent prüfen, ob die Durchführung randomisierter Studien möglich und angemessen ist. Kriterien wie Schweregrad und Häufigkeit der Erkrankung, Verfügbarkeit von Therapiealternativen, Praktikabilität und Angemessenheit bei der Studiendurchführung sowie spezielle Zulassungswege sind dabei zu berücksichtigen. Wird eine besondere Therapiesituation festgestellt, muss die bestmögliche Evidenz anerkannt und berücksichtigt werden. Ziel muss eine konsistente Bewertungssystematik sein, die regulatorische Realitäten abbildet und Innovationsanreize erhält. Das Beispiel zeigt, dass innovative Therapien trotz situationsangemessener Zulassung an zu starren Evidenzanforderungen der Nutzenbewertung scheitern können. Erforderlich ist daher die verbindliche Anerkennung der bestmöglichen Evidenz in besonderen Therapiesituationen. Prävention und Selbstmedikation stärken Apotheke, Arznei, Arzneimittel, Apotheker, Apothekerin, PTA, Ärztin, Symbolbild, Symbolfoto, Beruf, Gesundheitswesen, Drogerie, Frau, weiblich, erwachsen, Gespräch, Beratung, beraten, gesund, Gesundheit, Logo, Scheibe, Zeichen, Notfall, Hilfe, Versorgung, Erkrankung, Krank, Krankheit, Symbol, apotheke, arznei, arzneimittel, apotheker, apothekerin, pta, ärztin, symbolbild, symbolfoto, beruf, gesundheitswesen, drogerie, frau, weiblich, erwachsen, gespräch, beratung, beraten, gesund, gesundheit, logo, scheibe, zeichen, notfall, hilfe, versorgung, erkrankung, krank, krankheit, symbol, Apotheke, Arznei, Arzneimittel, Apotheker, Apothekerin, PTA, Ärztin, Symbolbild, Symbolfoto, Beruf, Gesundheitswesen, Drogerie, Frau, weiblich, erwachsen, Gespräch, Beratung, beraten, gesund, Gesundheit, Logo, Scheibe, Zeichen, Notfall, Hilfe, Versorgung, Erkrankung, Krank, Krankheit, Symbol Eigenverantwortung stärken und Effizienzpotenziale im Gesundheitssystem nutzen Eine nachhaltig wirksame Strukturreform muss auch die Prävention in den Fokus rücken. Angesichts des demografischen Wandels, weit verbreiteter chronischer Erkrankungen und begrenzter finanzieller Ressourcen kommt ihr seit Jahren eine hohe gesundheitspolitische Relevanz zu. Und doch werden die möglichen Potenziale noch nicht ausreichend genutzt. Eine konsequent umgesetzte Präventionspolitik trägt dazu bei, Krankheiten zu vermeiden oder Krankheitsverläufe einzudämmen und die Menschen besser am Leben zu beteiligen und somit langfristig Kosten zu senken, Produktivitätsverluste zu vermeiden und die Leistungsfähigkeit des Gesundheitswesens zu sichern. Präventionsleistungen umfassen auch Impfungen als tragende Säule der Primärprävention. Am Beispiel der Impfstoffversorgung zeigen sich die enormen ökonomischen Potenziale der Prävention sehr deutlich. Der errechnete Return of Investment für Erwachsenen-Impfstoffe liegt bei 19:1, das bedeutet, dass jedem ausgegebenen Euro gesamtgesellschaftliche Erträge in Höhe von 19 Euro entgegenstehen . Hinzu kommen ein ebenso starkes Innovationspotenzial sowie schnelle resiliente Produktionsstrukturen in Deutschland. Ein weiterer wichtiger Handlungshebel für eine strukturelle Neuausrichtung des Gesundheitssystems liegt im Ausbau der Selbstmedikation mit rezeptfreien Arzneimitteln. Dabei kommen Innovationen rezeptfreier Arzneimittel, z.B. Phytopharmaka, sowie dem sog. OTC-Switch, also der Entlassung geeigneter Arzneimittel aus der Verschreibungs- in die Apothekenpflicht, eine besondere Bedeutung zu. Dieser Ansatz stärkt die Eigenverantwortung von Patientinnen und Patienten und erschließt weitere Effizienzpotenziale. Auch in der Selbstmedikation liegt ein hoher gesundheitsökonomischer Wert, denn jeder Euro, der für Selbstmedikation ausgegeben wird, erspart dem GKV-System bereits heute 12 Euro und der Wirtschaft zusätzlich 3 Euro; aus gesellschaftlicher Sicht ergibt dies insgesamt eine Ersparnis in Höhe von 15 Euro. Zusätzlich werden mit der Selbstmedikation ärztliche Ressourcen geschont; mit jedem OTC-Switch und jeder neuen Zulassung noch mehr. Ziel: Prävention und Selbstmedikation stärken, um vermeidbare Krankheitslast zu reduzieren und Effizienzpotenziale im System zu heben. Schwerpunkte: Fokus auf die Vermeidung, statt der Behandlung von Krankheiten und damit die Zahl vermeidbarer Erkrankungen reduzieren Präventionspotenziale über Gesundheitsförderung, Früherkennung und Impfungen nutzen Impfungen weiter stärken als wichtige Säule der Primärprävention Selbstmedikation stärken, zzgl. Ausbau von OTC-Switches sowie Ermöglichung der Zulassung neuer rezeptfreier Arzneimittel Was jetzt zu tun ist: Selbstmedikation als tragende Säule der Gesundheitsversorgung anerkennen und ausbauen. OTC-Switch-Verfahren reformieren , um das derzeitige komplexe, langwierige und teils intransparente Verfahren zur Entlassung von Produkten aus der Verschreibungspflicht in die Apothekenpflicht zukünftig schlanker, planbarer und attraktiver zu gestalten. Hierzu liegt ein konkreter Vorschlag von Pharma Deutschland vor, der unter anderem im Rahmen der Stellungnahme zum GKV-Beitragssatzstabilisierungsgesetz (GKV BStabG ) eingebracht wurde. Behandlung von mäßig ausgeprägten entzündlichen, allergischen oder juckenden Hauterkrankungen (z. B. 1%-ige Hydrocortison-Creme; bisher nur niedrigere Wirkstärken als rezeptfrei erlaubt); kurzfristige Migränebehandlung (größere Packungen) und weitere Substanzen bzw. Indikationen wären für einen OTC-Switch denkbar. Rahmenbedingungen für die Zulassung und den Markzugang neuer rezeptfreier Arzneimittel, insbesondere Phytopharmaka, verbessern. Nationale Präventionsstrategie stärken mit verbindlichen Zielgrößen für Impfquoten . Dies umfasst auch, dass Public-Health Ziele im Bereich der Impfungen nicht durch zusätzlichen Sparinstrumente für Impfstoffe konterkariert werden, wie jüngst durch die neu etablierten Abschläge und das Preismoratorium für patentgeschützte Impfstoffe durch das GKV-Beitragssatzstabilisierungsgesetz (GKV-BStabG). Beschleunigung eines elektronischen Impfpasses und Impfmonitoring in Echtzeit. Vergütungs- und Bonusmechanismen für Krankenkassen bei Prävention verfolgen Anreizsystem zur Steigerung der Impfquoten schaffen, insbesondere durch einen Ausgleich bestehender Impfstoffkosten im Rahmen des Morbi-RSA (morbiditätsorientierter Risikostrukturausgleich). Schnelle und flächendeckende Implementierung des Impfens in Apotheken. Dauerhafte Finanzierung von Impfkampagnen. Impfungen als kritische Infrastruktur und Bestandteil nationaler Resilienzstrategien mitdenken und verankern. Datensilo im Bereich der Impfsurveillance (bspw. DEMIS) abbauen und im Rahmen des Gesundheitsdatennutzungsgesetzes harmonisieren sowie zugänglich machen. Einfacherer Zugang zu Impfungen im Rahmen der (vor-)stationären Behandlung, betriebsärztlicher Angebote und Pflege schaffen. Stärkung der Früherkennung von Krankheiten, auch über den weiteren Ausbau der Nutzung von Sekundärdaten und digitalen Ansätzen. Weiterentwicklung der Nutzenbewertung im Rahmen des AMNOG, um Arzneimittel bewerten zu können, deren hoher medizinischer Nutzen nicht durch die heutigen patientenrelevanten Endpunkte gemessen werden kann (siehe Beispiel Disease Interception). Präventionsmaßnahmen konsequent nach ihrem gesundheitlichen und volkswirtschaftlichen Nutzen evaluieren und erfolgreiche Maßnahmen nachhaltig finanzieren. Beispiel “Disease Interception” Ansatz: Prävention braucht Paradigmenwechsel Disease Interception beschreibt einen Ansatz, bei dem Krankheiten bereits in einer sehr frühen, präklinischen Phase erkannt und aufgehalten werden sollen. Das Konzept zielt selektiv auf bestimmte Risikogruppen, bei denen durch eine Früherkennung von Krankheitsprozessen der Diagnosezeitpunkt zeitlich nach vorne verlagert werden kann. Während klassische Prävention häufig größere Bevölkerungsgruppen unabhängig von ihrem individuellen Erkrankungsrisiko adressiert, setzt Disease Interception spezifisch an. Ziel ist es, Menschen mit einem besonders hohen Erkrankungsrisiko frühzeitig zu identifizieren, zu begleiten und krankheitsauslösende Prozesse bereits im präklinischen Stadium zu unterbrechen. Das Zeitfenster, in dem biologische Veränderungen bereits nachweisbar sind, Symptome aber noch nicht auftreten, kann genutzt werden, um Erkrankungen zu verhindern, verzögern oder in ihrem Verlauf deutlich abzumildern. Voraussetzung dafür ist ein Verständnis früher Krankheitsmechanismen, etwa durch Biomarker, molekulare Diagnostik, genetische Risikoprofile, digitale Anwendungen und die intelligente Nutzung von Gesundheitsdaten. Moderne Technologien und Künstliche Intelligenz eröffnen hier neue Möglichkeiten, individuelle Risiken präziser zu erfassen und gezielte Frühinterventionen abzuleiten. Innovative Ansätze wie die Disease Interception verdeutlichen einen grundlegend notwendigen Paradigmenwechsel. Statt Krankheiten erst nach Auftreten von Symptomen zu behandeln, müssen Krankheitsprozesse bereits in ihren frühesten Stadien erkannt und gezielt behandelt werden. Fortschritte in der molekularen Diagnostik, der Nutzung von Gesundheitsdaten und Künstlicher Intelligenz eröffnen die Möglichkeit einer präzisen, personalisierten Frühintervention. Damit kann Prävention von einem reaktiven zu einem proaktiven Ansatz weiterentwickelt werden mit dem Potenzial, Versorgungsergebnisse zu verbessern und die langfristige Nachhaltigkeit des Gesundheitssystems zu stärken. Disease Interception verbindet medizinische Innovation, Datennutzung und Prävention zu einem neuen Versorgungsverständnis. Richtig eingesetzt, kann dieser Ansatz dazu beitragen, Krankheitslast zu reduzieren, schwerwiegende Krankheitsverläufe zu vermeiden und Ressourcen im Gesundheitssystem gezielter einzusetzen. Prävention wird damit von einem eher allgemeinen Vorsorgeprinzip zu einem präzisen, personalisierten und innovationsgetriebenen Bestandteil einer nachhaltigen Gesundheitsversorgung weiterentwickelt. Das Beispiel zeigt, wie Disease Interception Prävention grundlegend neu denkt, indem es krankheitsauslösende Prozesse bereits im präklinischen Stadium bei klar definierten Hochrisikogruppen erkennt und gezielt unterbricht. Durch den Einsatz moderner Diagnostik, Datennutzung und Künstlicher Intelligenz kann Prävention von einem allgemeinen Vorsorgeprinzip zu einer präzisen, personalisierten Frühintervention weiterentwickelt werden, die Versorgungsergebnisse verbessert und die Nachhaltigkeit des Gesundheitssystems stärkt. Dokumente Pharma Deutschland: Strategie für eine zukunftsfähige Arzneimittelversorgung in Deutschland 13.08.2026 pdf 376 KB Erläuterungen: AMG (Arzneimittelgesetz): bildet den rechtlichen Rahmen für Arzneimittel in Deutschland. Es regelt unter anderem Zulassung, Herstellung, klinische Prüfung, Überwachung und Abgabe von Arzneimitteln, um Patientinnen und Patienten zu schützen. AMNOG (Arzneimittelmarktneuordnungsgesetz): regelt die frühe Nutzenbewertung neuer Arzneimittel in Deutschland. Der festgestellte Zusatznutzen bildet die Grundlage für die Preis- und Erstattungsverhandlungen zwischen Krankenkassen und Herstellern. AM-NutzenV (Arzneimittel-Nutzenbewertungsverordnung): regelt die Durchführung der frühen Nutzenbewertung neuer Arzneimittel in Deutschland. Sie definiert die Anforderungen an den Nachweis des Zusatznutzens gegenüber einer zweckmäßigen Vergleichstherapie. ATMP (Advanced Therapy Medicinal Products): Arzneimittel für neuartige Therapien. Dabei handelt es sich um innovative Arzneimittel, die auf Genen, Zellen oder Geweben basieren und häufig neue Behandlungsmöglichkeiten für schwere oder bislang nur eingeschränkt behandelbare Erkrankungen eröffnen. ALBVVG (Arzneimittel-Lieferengpassbekämpfungs- und Versorgungsverbesserungsgesetz): Gesetz zur Bekämpfung von Lieferengpässen bei patentfreien Arzneimitteln und zur Verbesserung der Arzneimittelversorgung, insbesondere bei Kinderarzneimitteln. Es reagiert auf zunehmende Lieferengpässe und soll die Versorgungssicherheit in Deutschland stärken. Besondere Therapiesituation : medizinische Konstellationen, in denen klassische randomisierte klinische Studien nicht oder nur eingeschränkt möglich sind. In solchen Fällen können andere wissenschaftliche Nachweise herangezogen werden, um den Nutzen einer Therapie zu bewerten Biosimilars sind hochähnliche Nachfolgepräparate biologischer Originalarzneimittel. Biotech Act (European Biotech Act): Initiative der EU zur Stärkung von Forschung, Entwicklung und Produktion im Bereich Biotechnologie. Ziel ist es, Innovationen schneller zu den Patientinnen und Patienten zu bringen, Investitionen zu fördern und Europas Wettbewerbsfähigkeit im globalen Biotechnologiesektor zu stärken. Critical Medicines Act : Gesetzesvorschlag der Europäischen Kommission, der darauf abzielt, die Versorgungssicherheit mit kritischen Arzneimitteln in Europa zu stärken. Dazu sollen die Produktion in der EU gefördert, Lieferketten widerstandsfähiger gemacht und die Abhängigkeit von einzelnen Lieferländern verringert werden. DEMIS : Deutsches Elektronische Melde- und Informationssystem für den Infektionsschutz. Es ermöglicht die digitale Meldung und Übermittlung von Infektionsdaten zwischen Laboren, Gesundheitsämtern und weiteren Behörden. Disease Interception : Ansatz der personalisierten Prävention, bei dem Krankheitsprozesse bereits vor dem Auftreten von Symptomen erkannt und gezielt aufgehalten werden sollen. EU-Kommunalabwasserrichtlinie (KARL) : auf europäischer Ebene als Urban Waste Water Treatment Directive (UWWTD) bekannt. Sie sieht die Einführung einer „vierten Reinigungsstufe“ zur Entfernung von Mikroverunreinigungen wie Arzneimittelrückständen und Bestandteilen von Kosmetika aus dem kommunalen Abwasser vor. Hersteller von Human-Arzneimitteln und Kosmetischen Mitteln sollen sich finanziell an den Kosten zur Einführung der 4. Klärstufe zur Entfernung von Mikroschadstoffen beteiligen. EU-HTA (European Health Technology Assessment) ist das europäische Verfahren zur gemeinsamen klinischen Bewertung neuer Gesundheitstechnologien. Ziel ist es, die Nutzenbewertung in Europa zu harmonisieren, Doppelbewertungen zu reduzieren und nationale Entscheidungen auf eine gemeinsame wissenschaftliche Grundlage zu stellen. EU-Verordnung 536/2014 (Clinical Trials Regulation, CTR) regelt die Durchführung klinischer Prüfungen mit Arzneimitteln in der Europäischen Union. Ziel ist es, Genehmigungsverfahren zu harmonisieren, die Transparenz zu erhöhen und klinische Forschung in Europa effizienter zu gestalten. Festbeträge sind Erstattungsobergrenzen der gesetzlichen Krankenversicherung für bestimmte Arzneimittelgruppen. Übersteigt der Arzneimittelpreis den Festbetrag, müssen Versicherte die Mehrkosten selbst zahlen. FuE (Forschung und Entwicklung) umfasst die wissenschaftliche Erforschung neuer Erkenntnisse sowie deren Umsetzung in innovative Produkte, Verfahren und Technologien. Generika sind wirkstoffgleiche Nachfolgepräparate von Originalarzneimitteln, die nach Patentablauf verfügbar werden. GKV-BStabG (GKV-Beitragssatzstabilisierungsgesetz): bündelt Maßnahmen zur Stabilisierung der Finanzen der gesetzlichen Krankenversicherung. Ziel ist es, Beitragssatzsteigerungen zu begrenzen und die Finanzierungsgrundlagen der Gesetzlichen Krankenkassen (GKV) zu sichern. Gold-plating bezeichnet nationale Zusatzregelungen, die über die Anforderungen des EU-Rechts hinausgehen und dadurch zusätzliche Bürokratie oder Belastungen für Unternehmen verursachen können. Impfsurveillance : systematische Erfassung, Auswertung und Überwachung von Daten zu Impfungen. Ziel ist es, Impfquoten, Wirksamkeit, Sicherheit und mögliche Versorgungslücken zu beobachten und die Wirksamkeit von Impfprogrammen zu bewerten. Internationale Preisreferenzierung : Verfahren, bei dem die Preise von Arzneimitteln in anderen Ländern als Grundlage für die nationale Preisfestsetzung oder Erstattung genutzt werden. MFG (Medizinforschungsgesetz): deutsches Gesetz zur Stärkung des Forschungs- und Pharmastandorts Deutschland. Es soll die Rahmenbedingungen für die Entwicklung, klinische Prüfung, Zulassung und Herstellung von Arzneimitteln und Medizinprodukten verbessern, Genehmigungsverfahren beschleunigen und den Zugang von Patientinnen und Patienten zu innovativen Therapien fördern. Morbi-RSA (morbiditätsorientierter Risikostrukturausgleich) ist ein Finanzausgleichssystem in der gesetzlichen Krankenversicherung (GKV) in Deutschland. Er verteilt die Gelder aus dem Gesundheitsfonds fair an die Krankenkassen, abhängig von Alter, Geschlecht und den tatsächlichen Krankheiten (Morbidität) der Versicherten. Most Economically Advantageous Tender (MEAT, „wirtschaftlich günstigstes Angebot“): Vergabeprinzip, bei dem öffentliche Auftraggeber Angebote anhand mehrerer Kriterien bewerten. Neben dem Preis fließen auch Faktoren wie Qualität, Versorgungssicherheit und Lieferkettenresilienz in die Entscheidung ein. Most Favored Nation (MFN)-Konzept (deutsch:„Meistbegünstigungsklausel“): ein Vertragspartner erhält mindestens die gleichen Konditionen wie der am günstigsten behandelte Vergleichspartner. Die US-Regierung unter Donald Trump nutzt dieses Prinzip in abgewandelter Form zur Arzneimittelpreisregulierung: Für bestimmte Medikamente sollen die USA künftig nicht mehr zahlen als den niedrigsten Preis, der in vergleichbaren OECD-Ländern gilt. MTMG-Wirkstoffe sind Wirkstoffe menschlicher, tierischer oder mikrobieller Herkunft sowie gentechnisch hergestellte Wirkstoffe. Für ihren Import aus Nicht-EU-Staaten gelten in Deutschland besondere arzneimittelrechtliche Anforderungen. Netflix-Modell : Vergütungsmodell, bei dem Hersteller wichtiger Arzneimittel eine feste jährliche Zahlung erhalten. Die Vergütung wird von der tatsächlichen Nutzung des Arzneimittels entkoppelt, um Forschung, Entwicklung und die Verfügbarkeit versorgungskritischer Medikamente langfristig abzusichern. Orphan Drugs : Arzneimittel für die Behandlung seltener Erkrankungen. Sie werden durch besondere europäische Regelungen gefördert, um die Entwicklung von Therapien für kleine Patientengruppen zu ermöglichen. Phytotherapeutika sind Arzneimittel auf pflanzlicher Basis. Sie enthalten Wirkstoffe aus Pflanzen oder Pflanzenteilen und werden zur Behandlung oder Vorbeugung von Erkrankungen eingesetzt. Preismoratorium verpflichtet Arzneimittelhersteller, Preissteigerungen oberhalb eines gesetzlich festgelegten Referenzpreises durch Abschläge an die Krankenkassen auszugleichen. Es dient der Begrenzung der Arzneimittelausgaben in der Gesetzlichen Krankenversicherung (GKV). Rabattverträge sind Vereinbarungen zwischen Krankenkassen und Arzneimittelherstellern, die Preisnachlässe für bestimmte Arzneimittel regeln und so die Ausgaben der gesetzlichen Krankenversicherung reduzieren. Real-World-Daten (RWD): Gesundheits- und Versorgungsdaten, die im Behandlungsalltag außerhalb klinischer Studien entstehen. Sie helfen dabei, den Einsatz und die Wirkung von Therapien unter realen Bedingungen zu bewerten. Repurposing : Erforschung und Nutzung bereits bekannter Wirkstoffe für neue medizinische Anwendungsgebiete. Dadurch können innovative Therapien häufig schneller und kostengünstiger entwickelt werden. Selbstmedikation bezeichnet die eigenverantwortliche Anwendung rezeptfreier Arzneimittel und Gesundheitsprodukte zur Vorbeugung, Linderung oder Behandlung von Beschwerden. Die Beratung in der Apotheke unterstützt eine sichere und wirksame Anwendung. SoHO-Verordnung ist ein europäischer Rechtsrahmen für Substanzen menschlichen Ursprungs. Sie schafft einheitliche Qualitäts-, Sicherheits- und Rückverfolgbarkeitsstandards, um Spenderinnen und Spender sowie Empfängerinnen und Empfänger besser zu schützen. Switch-Verfahren (OTC-Switch) ist das Verfahren zur Entlassung geeigneter Arzneimittel aus der Verschreibungspflicht. Ziel ist es, Patientinnen und Patienten einen einfacheren Zugang zu sicheren und wirksamen rezeptfreien Arzneimitteln zu ermöglichen.
12.08.2026
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DRAFT MDCG 2026-XX
Clinical evaluation under Regulation (EU) 2017/745 a guide for manufacturers and notified bodies
xxxx 2026
[bookmark: _Hlk161854405]Medical Device
Medical Device Coordination Group Document MDCG 2024-XX
This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law
page 35 of 98Restricted Information and Basic Personal Data
Table of contents
1. Introduction 5
2. Scope 5
3. References 5
4. Definitions 8
5. Abbreviations 13
6. General principles of clinical evaluation 14
6.1. What is clinical evaluation? 14
6.2. When is clinical evaluation undertaken and why is it important? 15
6.2.1. Clinical evaluation undertaken during the development of a medical device 16
6.2.2. Clinical evaluation for initial CE-marking 16
6.2.3. Clinical evaluation of devices bearing a CE mark 17
6.3. How is a clinical evaluation performed? 17
6.4. Who should perform the clinical evaluation? 19
7. Establishing a clinical evaluation (Stage 0) 21
7.1. General considerations 21
7.2. Specific considerations for the clinical evaluation of certain device categories 23
7.2.1. Implantable and class III devices (application of art. 61 (4)-(6)) 23
7.2.2. Annex XVI products 23
7.2.3. Custom made devices 23
7.2.4. Legacy devices 24
7.2.5. Medical device software 24
7.2.6. Devices for which demonstration of conformity based on clinical data is not deemed appropriate 24
7.2.7. Devices for unmet medical needs 25
7.3. Consultation by the manufacturer of an expert panel under Article 61(2) 25
8. Identification of clinical data (Stage 1) 26
8.1. Clinical data – Article 2(48) in MDR 26
8.1.1. Source of data - clinical investigations 26
8.1.2. Source of data - studies other than clinical investigations 27
8.1.3. Source of data - reports on other clinical experience 27
8.1.4. Source of data - Clinically relevant information coming from the PMS system, in particular the PMCF 28
8.2. Real-World Data 29
8.3. Clinical data generated and held by the manufacturer 30
8.4. Clinical data not held by the manufacturer 30
8.5. Data outside the definition of Article 2(48) 31
9. Appraisal of relevant clinical data (Stage 2) 33
9.1. General considerations 33
9.2. Appraisal plan 33
9.3. Conduct of the appraisal 34
9.3.1. Assessment of scientific validity of clinical data 35
9.3.1.1. Data sourced from clinical investigations 35
9.3.1.2. Data from studies other than clinical investigations 40
9.3.1.3. Data from reports on other clinical experience of the device 40
9.3.1.4. Data from clinically relevant information generated from the PMS system 40
9.3.2. Assessment of the relevance of a data set for the clinical evaluation 42
9.3.3. How to weight the contribution of each data set 44
10. Analysis of relevant clinical data (Stage 3) 48
10.1. Comprehensive analysis of all relevant clinical data 48
10.2. Clinical evidence for conformity with relevant GSPRs 49
10.3. Determining the requirement for new or additional clinical data 49
11. Generation of new or additional clinical data (Stage 4) 51
11.1. Pilot and pivotal pre-market clinical investigations 51
11.1.1. Pilot (early-stage, pre-market) clinical investigations 51
11.1.2. Pivotal (confirmatory, pre-market) clinical investigations 52
12. The clinical evaluation report (Stage 5) 53
12.1. Clinical evaluation documentation 54
13. Post Market Clinical Follow-Up 56
13.1 PMCF studies 57
13.2 PMCF investigations 59
13.3 Clinical investigations under MDR Article 74(2) 59
14. Update the clinical evaluation and associated documentation throughout the lifecycle of the device 60
14.1. General considerations on updating the clinical evaluation 60
14.2. Frequency of updates 61
15. The role of the notified body in the assessment of clinical evaluation reports 64
15.1. Art 54 (1) devices: Clinical evaluation consultation procedure 64
Appendices 67
A1. State of the art for the clinical evaluation 67
A1.1 When to identify State of the Art 67
A1.2 Identification of data and information (literature searches) 68
A1.3 Documenting 68
A2. Device description - typical contents 70
A3. Clinical evaluation plan typical content 72
A4. Clinical data for medical device software 74
A5. Sources of clinical data not held by the manufacturer (literature) 75
A6. Identification of available clinical data not held by the manufacturer, key elements for literature searches 77
A6.1 Methods 77
A6.2 Search protocol and report 78
A7. Appraisal of relevant clinical data - examples of studies that lack scientific validity for demonstration of clinical performance and/or clinical safety 80
A8. Use of data from retrospective studies 82
A9. Relationship between GSPRs and clinical evaluation process 84
A9.1 General considerations for GSPRs that potentially require clinical data for confirmation of conformity 85
A9.2 Evaluation of the undesirable side-effects 92
A9.3 Evaluation of the acceptability of the benefit-risk profile 93
A10. How to specify and justify the level of clinical evidence necessary 96
A11. Clinical evaluation report - proposed table of contents, examples of contents 99
A12. Proposed checklist for the release of the clinical evaluation report 107
[bookmark: _Toc446499021][bookmark: _Ref170995916][bookmark: _Toc236912863]Introduction
Pursuant to Chapter VI of Regulation (EU) 2017/745, hereafter referred to as the Medical Device Regulation (MDR), the confirmation of conformity with relevant General Safety and Performance Requirements (GSPRs) for a medical device must include a clinical evaluation, which is conducted in accordance with article 61 and Annex XIV to MDR. This document promotes a common approach to clinical evaluation for devices regulated by MDR.
The depth and extent of clinical evaluations should be flexible and appropriate to the nature, classification, intended purpose, and risks of the device in question as well as to the manufacturer’s claims in respect of the device. Therefore, this guidance is not intended to impose device-specific requirements. This document uses the terms "must", "shall", "have to" where these terms are used in the Regulation. "Should" is used in other instances. The terms "medical device" and "device" are used synonymously in this guidance document.
This guidance document replaces MEDDEV 2.7.1 rev 4.
[bookmark: _Toc446499022][bookmark: _Toc236912864]Scope
This guide is not legally binding; only the text of MDR is authentic in law. It is recognised that under given circumstances, for example as a result of scientific developments, an alternative approach may be possible or appropriate to comply with the legal requirements. Nevertheless, due to the participation of interested parties and of experts from national competent Authorities, it is anticipated that this guide will be followed within the Member States, thereby supporting uniform application of relevant provisions of EU Regulation and common practices. This guide is regularly updated according to regulatory developments. The latest version of the guide should always be used.
This guidance document and the requirements for clinical evaluation apply to all types of devices mentioned in art. 1(4) of MDR, i.e. medical devices, accessories for medical devices, and products listed in Annex XVI referred to as “devices”. This guidance does not concern in-vitro diagnostic devices.
[bookmark: _Toc446499023][bookmark: _Toc236912865]References
European Legislation:
· Commission Regulation (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Directives)
· Commission Implementing Regulation (EU) 2022/2346 of 1 December 2022 laying down common specifications for the groups of products without an intended medical purpose listed in Annex XVI to Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices
· Commission Implementing Decision (EU) 2019/1396 of 10 September 2019 laying down the rules for the application of Regulation (EU) 2017/745 of the European Parliament and of the Council as regards the designation of expert panels in the field of medical devices
· Regulation (EU) 2023/607 of the European Parliament and of the Council of 15 March 2023 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices
- Commission Regulation 722/2012 of 8 August 2012 concerning medical devices manufactured utilising tissues of animal origin
Harmonised and International standards:
- ISO 14155:2020 Clinical investigation of medical devices for human subjects – Good clinical practice
- EN ISO 14971:2019/A11:2021 Medical devices – application of risk management to medical devices
- EN ISO 62366-1 Application of usability engineering to medical devices
- EN ISO 60601-1-6 Medical electrical equipment
European guidance documents:
· MDCG 2019-3 rev.1 Clinical evaluation consultation procedure exemptions Interpretation of article 54(2)b
· MDCG 2019-9 - Rev.1 Summary of safety and clinical performance
· MDCG 2019-15 rev.1 guidance notes for manufacturers of class I medical devices
· [bookmark: _Hlk171954498]MDCG 2020-1 Guidance on clinical evaluation (MDR) / Performance evaluation (IVDR) of medical device software
· MDCG 2020-5 Guidance on clinical evaluation – Equivalence
· MDCG 2020-6 Guidance on sufficient clinical evidence for legacy devices
· MDCG 2020-7 Guidance on PMCF plan template
· MDCG 2020-8 Guidance on PMCF evaluation report template
· MDCG 2021-3 Questions and answers on custom made devices
· MDCG 2020-13 Clinical evaluation assessment report template
· MDCG 2021-6- Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation
· MDCG 2022-21 - Guidance on Periodic Safety Update Report (PSUR) according to Regulation (EU) 2017/745 - December 2022
· MDCG 2023-3 - Questions and Answers on vigilance terms and concepts as outlined in the Regulation (EU) 2017/745 on medical devices
· MDCG 2023-6 - Guidance on demonstration of equivalence for Annex XVI products - A guide for manufacturers and notified bodies
· MDCG 2023-7 – Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4)-(6) MDR and on sufficient levels of access’ to data needed to justify claims of equivalence
· MDCG 2024-10 Clinical evaluation of orphan medical devices
· MDCG 2025-10 Guidance on post-market surveillance of medical devices and in vitro diagnostic medical devices
Please be aware that additional guidance documents relevant to medical devices can be found here: https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en
Other guidance documents:
· IMDRF MDCE WG/N56 FINAL:2019 Clinical evaluation
· IMDRF MDCE WG/N65 FINAL:2021: Post-Market Clinical Follow-Up Studies
· IMDRF/GRRP WG/N47 FINAL 2024: Essential Principles of Safety and Performance of Medical Devices and IVD Medical Devices
· IMDRF MDCE WG/N57 FINAL 2019: Clinical Investigation
· IMDRF MDCE WG/N55 FINAL:2019 Clinical Evidence - Key Definitions and Concepts
· EMA/CHMP/578661/2010: European Medicines Agency recommendation on the procedural aspects and dossier requirements for the consultation of the European Medicines Agency by a notified body on an ancillary medicinal substance or an ancillary human blood derivative incorporated in a medical device or active implantable medical device
· EMA/426390/2021: Guideline on registry-based studies
· Guidance for best practices for clinical trials. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO.
This list contains documents available at the time this MDCG document was published. In general, the most recent versions of standards and legal texts should be used. In accordance with Recital 5 of MDR, certain references to International Medical Device Regulatory Forum (IMDRF) guidance documents and terminology included therein have been taken into account.
[bookmark: _Toc446499024][bookmark: _Ref164068428][bookmark: _Ref164068488][bookmark: _Ref167359734]
[bookmark: _Toc236912866]Definitions
Adverse event: any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational medical device. [Article 2(57) MDR]
Benefit-risk determination means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer. [Article 2(24) MDR]
Bias: systematic deviation of an outcome measure from its true value, leading to either an overestimation or underestimation of a treatment’s effect, or the diagnostic ability of the device. It can originate from, for example, the way patients are allocated to an intervention, the way the outcomes are measured and interpreted, and the way data are recorded and reported. [Adapted from GHTF SG5/N2R8:2007]
Clinical benefit: the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health; [Article 2(53) MDR]
Note: clinical benefits may be either directly or indirectly measurable; for example, devices such as guidewires may assist other medical devices in achieving their intended purpose, without having a direct therapeutic or diagnostic function themselves. These indirectly measurable benefits may require surrogate endpoints.
[bookmark: _Hlk126234879]Clinical data: information concerning safety or performance that is generated from the use of a device and is sourced from the following:
- clinical investigation(s) of the device concerned,
- clinical investigation(s) or other studies reported in the scientific literature, of a device for which equivalence to the device in question can be demonstrated,
- reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,
- clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up.
[Article 2(48) MDR]
Clinical evaluation: a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer; [Article 2(44) MDR]
Clinical evidence: clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer; [Article 2(51) MDR]
Clinical investigation: systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device. [Article 2(45) MDR]
Note: in the international standard EN ISO 14155:2020 'clinical trial' or ' clinical study' are synonymous with ' clinical investigation'. However, it should be acknowledged that the terms are not used synonymously in EU legislation, and for the purpose of this guidance, the term clinical investigation is used, in line with MDR definition (see also MDCG 2021-6 for more details).
Clinical investigation plan: document that describes the rationale, objectives, design and methodology, monitoring, statistical considerations, organisation and conduct of the clinical investigation. [Article 2(47) MDR]
Clinical performance: the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; [Article 2(52) MDR]
Clinical safety: freedom from unacceptable risks to a patient and/or user, when using the device according to its intended purpose and the manufacturer’s instructions for use.
Note: In exceptional cases where an instruction for use is not required, the collection, analysis and assessment of clinical data are conducted taking into account generally recognised modalities of use.
Clinical use: use of a device in or on living human subjects.
Note: Includes use of a medical device that does not have direct patient contact.
Device lifetime: the time period defined by the manufacturer in the device documentation during which the device is expected to remain safe and effective for use / in use.
Device deficiency: any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer; [Article 2(59) MDR]
Equivalent device: a device for which equivalence to the device under evaluation can be demonstrated, taking into account the clinical, technical and biological equivalence criteria described in MDR Annex XIV Section 3. [Derived from MDR Annex XIV, part A]
Note: further guidance on equivalence is provided in MDCG 2020-5; these concepts related to equivalence are considered equally applicable to legacy devices (devices previously CE marked under the European Medical Devices Directive 93/42/EEC or Active Implantable Medical Devices Directive 90/385/EEC) and new devices.
Evaluator: appropriately qualified individual appointed by the manufacturer to carry out the clinical evaluation process under its responsibility.
Harmonised standard: a European standard adopted on the basis of a request made by the Commission for the application of Union harmonisation legislation [point (1)(c) of Article 2 of Regulation (EU) No 1025/2012];
Hazard: potential source of harm. [EN ISO 14971:2019/A11:2021]
Incident: any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; [Article 2(64) MDR]
[bookmark: _Hlk167800110]Indication, indication for use: refers to the clinical condition that is to be diagnosed, predicted, prevented, monitored, treated, alleviated, compensated for, replaced, modified or controlled by the medical device. It should be distinguished from ‘intended purpose/intended use’, which describes the effect of a device. All devices have an intended purpose/intended use, but not all devices have an indication (e.g. medical devices with an intended purpose of cleaning, disinfection or sterilisation of devices). [MDCG 2020-6].
Information materials supplied by the manufacturer: for the purpose of this document, this refers to the labelling, instructions for use, promotional materials and, where applicable implant card and SSCP for the device under evaluation. [Derived from MDR Article 2(12), article 18(1) and Annex I Section 23]
Intended purpose: the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation, including and the claims of the manufacturer; [ Article 2(12) MDR].
Note 1: MDR defines ‘intended purpose’, but not ‘intended use’. ‘Intended use’ should be considered to have the same meaning as ‘intended purpose’. [MDCG 2020-6].
Note 2: Annex I point 23.4(b) requires that the intended purpose is included in the IFU with a clear specification of, as appropriate, indications, contra-indications, the patient target group or groups, and the intended users. Therefore, the intended purpose should specify these aspects as appropriate.
Level of clinical evidence: this terminology is used in MDR with respect to requirements for demonstration of conformity with the relevant GSPRs and overall benefit-risk. It is understood to encompass the amount and quality of evidence (i.e. its characterisation by quality, quantity, completeness and statistical validity, etc.) required to demonstrate safety, performance and the benefit-risk conclusion of a medical device. It should not be confused with the term ‘levels of evidence’ (as used in evidence-based medicine) which is used to rank study designs and is only a part of the concept ‘level of clinical evidence’.
Performance: the ability of a device to achieve its intended purpose as stated by the manufacturer. [Article 2(22) MDR]
Post-market surveillance: all activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions. [Article 2(60) MDR]
Real-World Data: data relating to patient health status and/or the delivery of health care collected from a variety of sources in routine clinical practice [footnoteRef:2].
. U.S. Food and Drug Administration (FDA) CfDaRH. Use of real-world evidence to support regulatory decision-making for medical devices guidance for industry and food and drug administration staff U.S. food and drug administration (FDA), 2017. https://www.fda.gov/media/99447/download
See also IMDRF documents.
Real-World Evidence: clinical evidence derived from analysis of real-world data.1
Registry: an organised system that uses observational methods to collect defined clinical data under normal conditions of use relating to one or more devices to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure and that serves predetermined scientific, clinical or policy purpose(s). [derived from ISO 14155]
Note 1: the term “register” and “registry” are considered synonymous for the purpose of this guidance document.
Note 2: there are several types of registries, for example patient registry, disease registry, device registry.
Risk: combination of the probability of occurrence of harm and the severity of that harm.
[ Article 2(23) MDR]
Risk management: systematic application of management policies, procedures and practices to the tasks of analysing, evaluating, controlling and monitoring risk. [EN ISO 14971:2019/A11:2021]
Scientific validity / scientifically valid: the association of a study, evaluation or other process and its results with reality and real-world outcomes.
Note: scientific validity encompasses both internal and external validity. [see Section 9]
Serious adverse event: any adverse event that led to any of the following:
a) death,
b) serious deterioration in the health of the subject, that resulted in any of the following:
1) life-threatening illness or injury,
2) permanent impairment of a body structure or a body function
3) hospitalisation or prolongation of patient hospitalisation,
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function,
5) chronic disease,
c) foetal distress, foetal death or a congenital abnormality or birth defect. [Article 2.58 MDR]
[bookmark: _Hlk126239436]Similar devices: devices belonging to the same generic device group. MDR defines the generic device group as a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics. [MDCG 2020-6]
State of the art: developed stage of current technical capability and/or accepted clinical practice in regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience.
Note: The state of the art embodies what is currently and generally accepted as good practice in technology and medicine. The state of the art does not necessarily imply the most technologically advanced solution. The state of the art described here is sometimes referred to as the “generally acknowledged state of the art”. [IMDRF/GRRP WG/N47]
Sufficient clinical evidence: an amount and quality of clinical evidence to demonstrate the safety and clinical benefit of the device when used as intended by the manufacturer. [See Appendix 10]
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[bookmark: _Toc236912867]Abbreviations
CEAR: Clinical Evaluation Assessment Report
CECP: Clinical Evaluation Consultation Procedure
CER: Clinical Evaluation Report
CEP: Clinical Evaluation Plan
CDP: Clinical Development Plan
CIP: Clinical investigation Plan
CIR: Clinical investigation Report
CMD: Custom made device
GCP: Good Clinical Practice
GSPR: General Safety and Performance Requirements
IFU: Instructions For Use
IMDRF: International Medical Device Regulatory Forum
MDR: Medical Device Regulation
PMS: Post-Market Surveillance
PMCF: Post-Market Clinical Follow-Up
PSUR: Periodic Safety Update Report
QMS: Quality management system
RWD: Real-World Data
RWE: Real-World Evidence
SOTA: State of the Art
SSCP: Summary of Safety and Clinical Performance
[bookmark: _Toc446499026]
[bookmark: _Toc236912868]General principles of clinical evaluation
[bookmark: _Toc446499027][bookmark: _Toc236912869]What is clinical evaluation?
[bookmark: _Hlk164436940]Clinical evaluation is a systematic, planned and continuous process which aims to demonstrate the safety and performance of a medical device in its clinical use and the confirmation of conformity of the device with GSPRs when used as intended by the manufacturer.
Core purposes of the clinical evaluation are the proper determination of the benefit-risk profile for the intended purpose of the device under evaluation, covering all device sizes, variants, models and accessories, and demonstration of the acceptability of that benefit-risk ratio based on the SOTA in the medical fields concerned. To achieve this, the intended performance, including clinical benefits, and identified risks should be specified with regards to their nature, probability, extent, duration and frequency, as applicable. The requirements for clinical evaluation apply to all classes of medical devices.
Clinical evaluation is the responsibility of the manufacturer. The clinical evaluation documentation (see section 12.1) and its updates are elements of the technical documentation of the device under evaluation as referred to in MDR Annex II[footnoteRef:3] (except for custom-made devices, for which further details are given in Section 7.2.3)[footnoteRef:4].
Section 6.1, Annex II to MDR
Article 61(12) of MDR
For compliance with MDR:
· [bookmark: _Ref171955812]confirmation of conformity with relevant GSPRs set out in Annex I of MDR under the normal conditions of the intended use of the device, including the evaluation of the undesirable side-effects and the acceptability of the benefit-risk-ratio, shall be based on clinical data providing sufficient clinical evidence. The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant GSPRs. That level of clinical evidence shall be appropriate in view of the characteristics of the device (such as the risk associated with the device) and its intended purpose[footnoteRef:5].
Article 61(1) of MDR
· the clinical evaluation must follow defined and methodologically sound procedures as described in:
· Article 61 of MDR;
· Annex XIV part A of MDR4.
See Section 6.3 for information on how to perform the clinical evaluation.
where demonstration of conformity with GSPRs based on clinical data is not deemed appropriate in accordance with Article 61(10) of MDR, an adequate justification for any such exception shall be given. The justification, which can be provided only for class I, IIa, IIb devices (excluding implantable devices), shall be included in the technical documentation of the device under evaluation (see Section 7.2.6).
The following items should be aligned with each other[footnoteRef:6]:
See MDCG 2020-13
the information materials supplied by the manufacturer;
the clinical evaluation documentation[footnoteRef:7];
See section 12.1
the risk management file;
PMS documentation;
SSCP, where applicable.
Particularly, the following aspects should be adequately supported by sufficient clinical evidence:
the intended purpose described in the information materials supplied by the manufacturer (covering all indications and intended patient/user populations, where relevant);
confirmation of device lifetime[footnoteRef:8], where relevant;
The device lifetime is the time period specified by the manufacturer in the device documentation during which the device is expected to remain safe and effective for use / in use. See MDCG 2022-21 for more information
the clinical performance, including clinical benefits, described in the information materials supplied by the manufacturer (including, for example, any claims[footnoteRef:9] on performance and safety);
See Article 7 of MDR
safety of the device and measures for risk avoidance and risk mitigation described in the information materials supplied by the manufacturer (including, for example the disclosure of the residual risks, contraindications, precautions, warnings, undesirable side effects, instructions for managing foreseeable unwanted situations);
where relevant, the usability of the device for the intended users and the suitability of the information materials supplied by the manufacturer for the intended users (including, if applicable, for lay or disabled persons);
instructions for target population groups (for example vulnerable populations such as pregnant women, paediatric populations, elderly populations or immunocompromised populations).
[bookmark: _Toc446499028][bookmark: _Toc236912870][bookmark: _Hlk145430741]When is clinical evaluation undertaken and why is it important?
Article 10(3) of MDR requires manufacturers to conduct a clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF. The clinical evaluation, including PMCF, also needs to be addressed in the manufacturer’s quality management system (QMS) as per Article 10(9)(f) of MDR.
Clinical evaluation is conducted throughout the lifecycle of a medical device, as an ongoing process (see Section 14 regarding updating the clinical evaluation). MDR does not specify the exact timing for initiating a clinical evaluation and the timing is ultimately up to the manufacturer. It is most appropriate to start the clinical evaluation as early as possible such as during the development of a medical device in order to identify data that need to be generated for market access. Clinical evaluation is mandatory for initial CE-marking, and it must be actively updated thereafter as new information on the safety and performance of the medical device, including clinical benefits, is obtained during its use.
This information should be fed into the risk management process according to the harmonized standard EN EN ISO 14971:2019/A11:2021 and may result in changes to the manufacturer's risk assessment, CEP, clinical development plan, IFU and PMS activities.
Clinical evaluation is necessary and important because it ensures that the confirmation of safety and performance of the device is based on sufficient clinical evidence throughout its lifetime. This ongoing process enables manufacturers to provide notified bodies and competent authorities with sufficient clinical evidence for demonstration of conformity of the device with the GSPRs throughout its lifetime (for example for CE marking, fulfilment of post-market surveillance and reporting requirements, or during surveillance procedures).
[bookmark: _Toc446499029][bookmark: _Toc236912871]Clinical evaluation undertaken during the development of a medical device
Clinical evaluation is particularly relevant during the design phase to identify all relevant aspects of the device that may require clinical data.
Premarket research and development are guided by clinical evaluation and risk management. Typically, manufacturers carry out clinical evaluations to:
define needs regarding clinical safety and clinical performance (including requirements for demonstration of clinical benefit of the device;
in case of possible equivalence to an existing device, establish equivalence between the device and claimed equivalent devices and evaluate clinical data available for the claimed equivalent devices[footnoteRef:10];
MDCG 2020-5
carry out a gap analysis taking SOTA into consideration, define which data still need to be generated for the device under evaluation, and plan the clinical development, which includes, when necessary, clinical investigations and their study design (for additional information, see Section 10, Section 11 and Appendix A10).
The initial clinical evaluation is important to determine if premarket clinical investigation(s) are required. The justification for the design of a clinical investigation should be based on the results of the clinical evaluation, making it an important pre-cursor to the clinical investigation during the development phase[footnoteRef:11].
ISO 14155:2020 Section 6.3
[bookmark: _Toc446499030][bookmark: _Toc236912872]Clinical evaluation for initial CE-marking
Clinical evaluation is required for the conformity assessment process leading to signing the declaration of conformity, the CE-marking and placing on the market of a medical device. The purpose is to:
document that there is sufficient clinical evidence to demonstrate conformity with applicable GSPRs set out in Annex I under the normal conditions of the intended use of the device (see Appendix A9);
identify aspects that need to be addressed systematically during post-market surveillance (PMS), e.g. in PMCF activities required under MDR (see section 14).
[bookmark: _Toc446499031][bookmark: _Toc236912873]Clinical evaluation of devices bearing a CE mark
The clinical evaluation is a continuous process that needs to be updated throughout the device lifecycle with clinical data obtained from the implementation of the manufacturer's post-market surveillance plan, including a PMCF plan[footnoteRef:12] (see Section 14).
MDCG 2020-7
[bookmark: _Toc446499032][bookmark: _Ref164526404][bookmark: _Toc236912874] How is a clinical evaluation performed?
[bookmark: _Ref433562200][bookmark: _Toc446499033][bookmark: _Ref170141061]A clinical evaluation should be systematic, objective, reasoned. It should identify, appraise and analyse both favourable and unfavourable data.
Clinical evaluation is typically based on clinical data pertaining to the device under evaluation. MDR also provides a possibility to draw on the clinical experience regarding the safety and performance of an equivalent device to establish the clinical evidence[footnoteRef:13]. Equivalence shall be demonstrated according to MDR requirements[footnoteRef:14].
Article 61(3) and Section 3, Annex XIV of MDR
Section 3, Annex XIV to MDR. See MDCG 2020-5 for guidance on equivalence
MDR defines the discrete activities in performing a clinical evaluation[footnoteRef:15] (referred to as stages[footnoteRef:16] in this guidance):
Section 1, Part A, Annex XIV to MDR
Please note that MDR does not mandate the use of 'Stage 0,' 'Stage 1,' etc., terminology, which is optional.
· Stage 0: Taking into consideration the SOTA, establish a CEP including a clinical development plan (see Section 7 and Appendices A1, A2, A3, A10)
· Stage 1: Identify available clinical data relevant to the device and its intended purpose (see Section 8 and Appendices A6 and A7).
· Stage 2: Appraise all relevant clinical data by evaluating their suitability for establishing the safety and clinical performance of the device (see Section 9 and Appendices A7 and A8);
· Stage 3: Analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits (see Section 10 and Appendices A9) and identify any gaps in clinical evidence. In particular, conclusions are reached about:
· compliance with relevant GSPRs, including its benefit-risk profile taking into account the generally acknowledged SOTA,
· the contents of information materials supplied by the manufacturer,
· residual risks and uncertainties or unanswered questions (such as rare complications, long term performance, etc.), whether these are acceptable for CE-marking, and whether they are required to be addressed during PMS, through PMCF activities.
· Stage 4: Generate if needed, through properly designed clinical investigations, any new or additional clinical data necessary to address outstanding issues identified in stage 3 (see Section 11). Such new or additional clinical data should undergo Stages 2 and 3.
· Stage 5: Document the results of the clinical evaluation and the clinical evidence on which it is based in a clinical evaluation report (see Section 12 and Appendix A11).
Each of these stages is covered in separate sections later in this document (see Figure 1).
For initial CE marking following identification, appraisal, and analysis of existing clinical data, the manufacturer may determine that additional clinical data needs to be generated through properly designed clinical investigations (see Section 11). Once these clinical investigations are completed, the new data will then need to be appraised and analysed as per Stages 2 and 3 and documented in the CER. After CE marking and based on the conclusions of the clinical evaluation analysis stage additional clinical data may be collected through PMCF activities conducted in accordance with the manufacturer’s PMCF plan (see Section13). Based on this information, the clinical evaluation shall be updated throughout the lifecycle of the device concerned (see Section 6.2.3).
During the course of a clinical evaluation the stages are often iterative. For example, the appraisal and analysis stage may uncover new information and raise new questions, with a need to reconsider some aspects of the evaluation, refine the clinical evaluation plan, and to retrieve, appraise and analyse additional data.
[image: ]
[bookmark: _Ref172304485] Figure 1: Stages of a clinical evaluation and references to sections and appendices of this document.
[bookmark: _Toc236912875]Who should perform the clinical evaluation?
The clinical evaluation should be conducted by a suitably qualified evaluator or team of evaluators, each qualified for their respective task(s).
The manufacturer should take the following aspects into consideration:
the manufacturer defines requirements for the evaluators that are in line with the nature of the device under evaluation and its clinical performance and risks in their QMS.
the manufacturer should be able to justify the choice of the evaluators through reference to their qualifications and documented experience (for example, by demonstrating this through their curriculum vitae),
as a general principle the evaluator/team of evaluators should (collectively) possess knowledge of the following:
the device technology and its application;
diagnosis and management of the conditions which relate to the device intended purpose, knowledge of medical alternatives, treatment standards and technology (e.g. specialist clinical expertise in the relevant medical specialty);
relevant research methodology (e.g., clinical investigation design and biostatistics);
information management (e.g. scientific background or librarianship qualification; experience with relevant databases);
· regulatory requirements; and
medical writing (e.g. post-graduate experience in a relevant science or in medicine; training and experience in medical writing, systematic review and critical appraisal of clinical data).
Evaluators should have at least the following training and experience in the relevant field:
· a degree from higher education in the respective field and 5 years of documented professional experience; or
· 10 years of documented professional experience if a degree is not a prerequisite for a given task.
There may be circumstances where the level of evaluator expertise may be less or different; this should be documented and duly justified.
[bookmark: _Toc446499034][bookmark: _Ref164263127][bookmark: _Ref164263128][bookmark: _Ref165381637]
[bookmark: _Toc236912876]Establishing a clinical evaluation (Stage 0)
[bookmark: _Ref233792396][bookmark: _Toc236912877][bookmark: _Hlk164627924]General considerations
Manufacturers are required to establish a CEP to meet the requirements of MDR Annex XIV Section 1(a).
It is recommended the CEP define the scope of the clinical evaluation, which may include, depending on the stage in the lifecycle of the product:
identification and description of the device under evaluation covering all sizes, variants, model, accessories and configurations (see Appendix A2 for more information on the description content);
description of the SOTA (see Appendix A1). Note that the SOTA description may be documented in the CER or in a dedicated document.
whether the manufacturer intends to claim equivalence to another device. Demonstration of equivalence is documented in the CEP, in the CER or in a dedicated document (see MDCG 2020-5 for more information on equivalence).If equivalence is claimed, the manufacturer evaluate this equivalence and the level of access to the data regarding the clinical, technical and biological characteristics to be considered for the demonstration of equivalence (see Appendix II of MDCG 2023-7[footnoteRef:17] for more information on the hierarchy of level of access to this data).
While MDCG 2023-7 is specific to class III and implantable devices, the general principles may be applied to all devices
The CEP shall include at least the information listed in Annex XIV, part A, par 1(a) of MDR. Mandatory information together with some clarifying explanations are as follows:
a. an identification of the GSPRs that require support from relevant clinical data[footnoteRef:18]. According to art. 61(1) of MDR, confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device shall be based on clinical data providing sufficient clinical evidence. Relevant GSPRs requiring clinical data shall be identified case by case by the manufacturer for the device under evaluation.
See section 7.1.6 for devices falling under art. 61(10)
See appendix A9 for information on GSPRs potentially requiring clinical data.
b. a specification of the intended purpose of the device (see Appendix A2 for more information on the intended purpose content).
c. a clear specification of intended target groups with clear indications and contra-indications, where applicable.
d. a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters, including indirect benefits. Appendix A9 provides more information on clinical benefit and on the quantification of benefits and determination of relevant outcome parameters. Please note that, at this stage, only parameters should be identified without quantification.
e. a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects. Qualitative aspects of clinical safety are those assessed on a non-numerical basis, such as the nature of adverse events. Quantitative aspects of clinical safety are those involving the measurement and analysis of numerical data, such as the incidence rates of adverse events. The methods that are intended to be used to assess these aspects have to be clearly specified in the CEP. Such methods are those described later on in this guidance and may include:
· identification of clinical safety parameters based on:
- the residual risks and potential undesirable side effects identified during the risk management process of the device under evaluation.
- the SOTA (see A1). Note that from the SOTA both parameters and their quantification can be derived to be used as reference in the analysis stage.
· identification (see Section 8 and Ax), appraisal (see Section 9), and analysis (see Section 10) of clinical safety data for the device under evaluation or the equivalent device.
f. an indicative list and specification of parameters to be used to determine, based on the SOTA in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose of the device; MDR requires to create a list of parameters, which may be qualitative or quantitative and that serve as basis for evaluating the aspects, described in Appendix A9 relevant for the balance between the benefits and risks of the device taking into consideration the SOTA (for example, a mortality reduction of a certain percentage to demonstrate a positive impact on clinical outcome). Where quantitative parameters are identified, their acceptance criteria based on the state of art should also be specified. The indicative list may need to be refined during the device lifecycle to adjust for changes in the SOTA in medicine.
g. an indication of how benefit-risk issues relating to specific components, such as use of pharmaceutical products, non- viable animal tissues or human tissues, are to be addressed.
h. a clinical development plan (CDP). The CDP shall indicate the progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, with an indication of milestones and a description of potential acceptance criteria. In some cases, for example for legacy devices, it may be acceptable for CDP to be limited to PMCF activities, if duly justified.
i. reference to the PMCF plan with an indication of milestones and a description of potential acceptance criteria contained in the PMCF plan.
Planning of clinical evaluation stages 1-3 – the methods to be used for identification, appraisal and analysis of available clinical data as described in Sections 8, 9 and 10 - should also be specified in the CEP or in dedicated documents (see Section 12.1).
Moreover, as stated in MDR Article 61(1), the manufacturer must specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant GSPRs. This specification and justification should be included in the CEP (please see Appendix A10 for guidance on how to specify and justify the level of clinical evidence necessary). Once specified and justified, this can act as the minimum level to which the analysis (see Section 10) should compare and enables the manufacturer to determine whether the analysed clinical data provides sufficient clinical evidence in line with Article 61(1).
See Appendix A3 for CEP typical content.
[bookmark: _Toc236912878][bookmark: _Hlk145431572]Specific considerations for the clinical evaluation of certain device categories
[bookmark: _Toc158730992][bookmark: _Toc236912879] Implantable and class III devices (application of art. 61 (4)-(6))
Article 61(4) of MDR requires clinical investigations to be performed for implantable and class III devices. There are however four exemptions from this requirement as outlined in bullets 1-3 of paragraph (4) and in paragraphs (5), (6)(a) and (6)(b) respectively. For these cases there are circumstances under which it may be appropriate to use data coming from sources other than clinical investigations carried out on the device under evaluation. Clarifications on these matters are provided by MDCG 2023-7, MDCG 2020-5 and MDCG 2020-6.
In the case where a clinical investigation is determined to be mandatory, i.e., where none of the above-mentioned exemption applies, in order to obtain the needed clinical data to support the clinical evidence for a claimed indication MDR does not specify the number or extent of the clinical investigation(s) required. However, as a minimum, mandatory clinical investigation(s) should be understood to mean a pivotal clinical investigation(s) generating pivotal data (see Section 11.1). As such, exploratory investigations such as feasibility or first in man studies are not normally sufficient to meet the requirement for a mandatory clinical investigation.
[bookmark: _Toc151129063][bookmark: _Toc151129338][bookmark: _Toc151129960][bookmark: _Toc155681006][bookmark: _Toc158730993][bookmark: _Toc158731003][bookmark: _Toc236912880]Annex XVI products
MDR provides that the clinical evaluation of products without an intended medical purpose are to be based on relevant clinical data concerning performance and safety. Such data are to include information from PMS, PMCF, and, where applicable, specific clinical investigations. The general principles proposed by this guidance document are relevant for the clinical evaluation of Annex XVI products provided that the requirement to demonstrate the clinical benefit is understood as a requirement to demonstrate the performance of these products in accordance with Article 61(9). Following with the principles established in preamble (11) of Commission Implementing Regulation (EU) 2022/2346, the document MDCG 2023-6 “Guidance on demonstration of equivalence for Annex XVI products - A guide for manufacturers and notified bodies” clarifies how to demonstrate equivalence for Annex XVI products.
[bookmark: _Toc158731004][bookmark: _Ref163489758][bookmark: _Toc236912881]Custom made devices
As for any other medical device manufacturer, custom made devices’ manufacturers shall establish, document, implement, maintain, keep up to date and continuously improve a quality management system (QMS) that shall ensure compliance with MDR in the most effective manner that is proportionate to the risk class and the type of device[footnoteRef:19]. The QMS must address all elements described in Article 10(9) of MDR, including clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF. Therefore, Article 61(12), stating that the clinical evaluation report shall be part of the technical documentation referred to in Annex II except for custom-made devices, should not be interpreted as an exemption from performing clinical evaluation for CMDs. This paragraph only states that Annex II technical documentation does not need to be provided for CMDs[footnoteRef:20]. CMD manufacturers should apply these obligations to devices with the same intended purpose, materials used, process utilised, same principal design etc. and not to each individual CMD. For more information refer to MDCG 2021-3.
MDCG 2021-3, Q8
Article 10 (4)-(5) of MDR
[bookmark: _Toc155681018][bookmark: _Toc158731006][bookmark: _Toc236912882]Legacy devices
For specific aspects pertaining to clinical evaluation of legacy devices see MDCG 2020-6[footnoteRef:21].
Please note that this is valid until the end of the transition period as per MDR art. 120
[bookmark: _Toc236912883]Medical device software
For specific aspects pertaining to clinical evaluation of medical device software see MDCG 2020-1.
[bookmark: _Ref164526539][bookmark: _Toc236912884]Devices for which demonstration of conformity based on clinical data is not deemed appropriate
Where demonstration of conformity with GSPRs based on clinical data is not deemed appropriate, an adequate justification for any such exception must be given by the manufacturer in accordance with Article 61(10) of MDR in the CEP, which is part of the technical documentation referred to in Annex II of MDR. The justification must be based on the results of the manufacturer’s risk management and on consideration of the specifics of the interaction between the device and the human body, the intended clinical performance and the claims of the manufacturer. Article 61(10) is not applicable to class III or implantable devices.
For devices applying Article 61(10) of MDR, their CER should include at least the following information:
· a description of the SOTA (see Appendix A1), if not in the CEP or in a standalone document,
· a literature review of the device under evaluation,
· a summary of relevant non-clinical data, including results of non-clinical testing methods, performance evaluation, bench testing, and pre-clinical evaluation,
· due substantiation of the adequacy of demonstration of conformity with the GSPRs based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and preclinical evaluation,
· a plan for the evaluation of clinically relevant information coming from PMS and PMCF, if deemed appropriate.
Based on the above documentation, the notified body, when required by the conformity assessment procedure, will evaluate the acceptability of the justification provided in the CEP.
An example of a device that could potentially apply MDR Article 61(10) may be a device intended to sterilise other invasive medical devices prior to their use. For certain sterilisers, the performance may depend on reaching and maintaining specified values for process parameters; these could potentially be verified through non-clinical testing alone. Another example could include medical refrigerators that are intended for storing tissues and disinfectant solutions.
[bookmark: _Toc236912885]Devices for unmet medical needs
Like all medical devices, devices for unmet medical needs must fully comply with the GSPR to be CE-marked. Many of these devices may be orphan devices and/or breakthrough innovative devices.
Orphan medical devices
Guidance on orphan medical devices is provided in MDCG 2024-10 Clinical evaluation of orphan medical devices.
Breakthrough innovative devices for unmet medical needs
Guidance on breakthrough medical devices is provided in MDCG 2025-9 Clinical evaluation of breakthrough medical devices.
[bookmark: _Toc236912886]Consultation by the manufacturer of an expert panel under Article 61(2)
The expert panels for medical devices designated by the Commission Implementing Decision (EU) 2019/1396 may provide scientific advice to manufacturers of certain high-risk medical devices on their intended clinical development strategies and proposals for clinical investigations. According to Article 61(2) of MDR, the devices in scope of the expert panels’ advice are class III devices and class IIb active devices intended to administer and/or remove a medicinal product from the human body (see MDR Section 6.4 of Annex VIII (Rule 12) for the latter). It is for the applicant to determine the type and risk class of their device before submitting the request to the expert panels. The Secretariat for the expert panels for medical devices is managed by the European Medicines Agency. Note that per article 61(2), the manufacturer shall give due consideration to the views expressed by the expert panel, and such consideration shall be documented in the clinical evaluation report.
[bookmark: _Toc446499035][bookmark: _Ref164155827][bookmark: _Ref164263102][bookmark: _Ref165303089][bookmark: _Ref166607147][bookmark: _Ref170135872][bookmark: _Ref170135907][bookmark: _Ref170994888]
[bookmark: _Toc236912887]Identification of clinical data (Stage 1)
The goal of this stage is to identify available clinical data that are relevant to the device under evaluation, for the purpose of clinical evaluation. Relevant data that are identified in this stage will undergo appraisal in line with Stage 2 (Section 9). For specifics relating to MDSW, see Appendix A4.
[bookmark: _Ref164261395][bookmark: _Ref164356469][bookmark: _Toc236912888][bookmark: _Hlk158301978]Clinical data – Article 2(48) in MDR
[bookmark: _Hlk201755655]As defined in MDR Article 2(48), data can and must be considered as clinical data if the data concerns the safety or performance of the device, are generated from the use of the device or equivalent device and are sourced from one or more of the four sources specified in the four indents stated in MDR Article 2(48).
Further guidance on the interpretation of Article 2(48) is given below.
[bookmark: _Ref164180578][bookmark: _Toc236912889]Source of data - clinical investigations
Clinical investigations[footnoteRef:22] are defined in MDR Article 2(45) and include those pursuant to MDR Article 62, 74 and 82, as well as clinical investigations conducted under the medical device directives[footnoteRef:23], and clinical investigations conducted outside the European Union if they meet the definition of Article 2(45) (See Section 9.3.1.1 for more information on Clinical investigations based outside of the EU). Guidance on the conduct of clinical investigations is available in other MDCG documents[footnoteRef:24] as well as ISO 14155.
Note the specifics of indents one, two, and four of Article 2(48), respectively: Data sourced from clinical investigations of the device under evaluation fall under the first and data sourced from clinical investigations of an equivalent device fall under the second indent of Article 2(48). Clinical investigations that are conducted or identified as a part of the PMS and PMCF, qualify as sources of clinical data by way of the fourth indent of the clinical data definition in Article 2(48).
Directive 93/42/EEC and Directive 90/385/EEC
Available via: https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en
There is no requirement for publication of clinical investigations to be considered as source of clinical data. For more guidance on clinical investigations, see MDCG 2021-6.
Note that retrospective studies do not fall under the definition of clinical investigations[footnoteRef:25], but may be considered as sources of clinical data if they fall under any of the other indents of Article 2(48) (described below).
See MDCG 2021-6 Rev.1
[bookmark: _Toc236912890][bookmark: _Hlk201830100]Source of data - studies other than clinical investigations
Studies other than clinical investigations are clinical studies within medical research involving human subjects that have clear research objectives and endpoints but fall outside the Article 2(45) definition of clinical investigation[footnoteRef:26].
See MDCG 2021-6 Rev.1
Note that for the clinical evaluation of non-CE-marked devices, data from studies other than clinical investigations of the device under evaluation fall under the definition of clinical data only if published in peer-reviewed scientific literature[footnoteRef:27], or of the equivalent device, only if published in scientific literature[footnoteRef:28].
Indent three Article 2(48) MDR
Indent two Article 2(48) MDR
Note that for the clinical evaluation of CE-marked devices data from studies other than clinical investigations of the device under evaluation and/or an equivalent device fall under the definition of clinical data without requirements of publication[footnoteRef:29].
Indent four Article 2(48) MDR
Examples of “other studies” include (list not exhaustive):
· a retrospective study using data generated from the use of a device,
· a study using real-world data collected from a registry (see section 8.2 for more information on real-world data),
· a study where a device is used but the scope of the study is not to assess the safety or performance of the device(s)[footnoteRef:30]:
Any device which is used for medical purposes as per Article 2(1) needs to comply with MDR. If conducted with a CE-marked device this would fall under indent four and would not need to be published.
· a clinical trial of a medicinal product that involves determining blood pressure or oxygen saturation that will require the use of a device, or
· a study with primary focus on stent/stent delivery systems in which the guidewire is used in the PTCA/PTA[footnoteRef:31] procedure The study’s primary focus is on the stent with relevant safety and performance data gathered indirectly for the guidewire.
PTCA is short for Percutaneous Transluminal Coronary Angioplasty), PTA is short for Percutaneous Transluminal Angioplasty
[bookmark: _Toc236912891][bookmark: _Ref164180629]Source of data - reports on other clinical experience
[bookmark: _Hlk201830171]Data sourced from reports on other clinical experience of the device under evaluation and/or equivalent device falls under indent three of Article 2(48). Reports on other clinical experience refer to data generated through routine clinical use of the device under evaluation or of an equivalent device, but not within the context of clinical investigations and other studies[footnoteRef:32].
For an equivalent device, other studies fall under indent two.
Note that, for the clinical evaluation of a non-CE marked device, reports on other clinical experience fall under the definition of clinical data only if published in peer-reviewed scientific literature[footnoteRef:33]. The requirement for publication in peer-reviewed scientific literature does not apply to information sourced from PMS and PMCF, activities of a CE-marked device[footnoteRef:34],.
Indent three Article 2(48) MDR
Indent four Article 2(48) MDR
Examples of reports on other clinical experience that may qualify as clinical data include (list not exhaustive):
· reports presenting data from high quality surveys[footnoteRef:35] regarding the use of a non-CE-marked device in other jurisdictions where the device is marketed (with the same intended purpose and use)
Planning, designing and implementing high-quality (Level 4) post-market clinical follow-up surveys. Journal of Medical Device Regulation, 2023, 20(4), 31–44
· reports on real-world data (RWD) generated using a device in other jurisdictions outside of the EU, such as analysis of data that has been extracted from vigilance databases/registries and data collected from hospital information systems (see section 8.2).
[bookmark: _Ref233793815][bookmark: _Toc236912892][bookmark: _Ref164071257][bookmark: _Ref165299447][bookmark: _Ref165303170]Source of data - Clinically relevant information coming from the PMS system, in particular the PMCF
Clinically relevant information collected through PMS and PMCF, falls under indent four of MDR Article 2(48).
Note that there is no requirement for clinical data collected or generated from PMS and PMCF, to be published. Therefore, data that do not fit the definition of clinical data as per indent two and three due their unpublished nature may qualify as clinical data through indent four if generated as a part of the PMS of a CE-marked device.
PMS data and PMCF data may include clinical data of equivalent and similar devices.
The collection of data through PMS and PMCF, is an MDR requirement (Articles 83-86) and it refers to data collected for devices placed on the market[footnoteRef:36] or put into service[footnoteRef:37] in accordance with MDR[footnoteRef:38]. For non-CE marked devices approved in other jurisdictions, data would need to fall under any of indents 1-3 in Article 2(48) to be considered as clinical data. Examples of what constitutes “clinically relevant information” from PMS and PMCF are described in MDR Annex III section 1(a), and in MDR Annex XIV Part B 6.1-6.2, respectively[footnoteRef:39].
Article 2(28) MDR
Article 2(29) MDR
Note that this includes data for CE-marked devices within EEA and countries that have a mutual recognition agreement for the application regarding MDR.
Guidance on the expectations on the PMS can be found in MDCG 2025-10 Guidance on post-market surveillance of medical devices and in vitro diagnostic medical devices and in MDCG 2022-21 Guidance on PSUR. PSUR is mandatory for class IIa, IIb and III devices, whereas manufacturers of class I devices do not have to prepare a PSUR; instead, they should prepare a Post-Market Surveillance Report (PMSR) . MDCG 2022-21, although not covering PMSR, may provide useful suggestions on how information can be presented. Guidance on PMCF can be found in MDCG 2020-7 and 2020-8.
Examples of clinically relevant information from PMCF are (list not exhaustive):
· data from PMCF activities, such as PMCF investigations and other clinical studies (see section 13.
· RWD from clinical experience such as data from registries[footnoteRef:40] generated post-market (see section 9.3.1.4);
See IMDRF/Registry WG/N46 FINAL:2018 Tools for Assessing the Usability of Registries in Support of Regulatory Decision-Making for guidance on e.g., key processes and features to be considered in assessing the usability of registry data for regulatory purposes
· Data from high quality surveys for users and/or patients.
· screening of scientific literature; and
· data from off-label use or misuse (see below) [footnoteRef:41].
Required as part of the PMCF plan by XIV Part B 6.1.(e)
MDR requires that possible systematic misuse or off-label use of the device are identified through PMCF activities with a view to verifying that the intended purpose is correct. This information may prompt the manufacturer to evaluate whether corrective actions are needed to reduce or eliminate the occurrence of this misuse, or it may prompt the manufacturer to consider whether expansion of the intended purpose to include this currently off-label use may be appropriate. Note that PMCF data from off-label use is not sufficient to support the justification of extending the intended purpose to incorporate this new use or indication, and additional non-clinical and clinical data, such as additional pre-clinical testing and clinical investigation(s) conducted in line with MDR Article 74(2), would be needed. However, in the case of legacy orphan devices, as described in MDCG 2024-10, it might be acceptable to consider clinical data from off-label use when considering revision or expansion of a device’s intended purpose to include this use/indication.
[bookmark: _Toc236912893]Real-World Data
Real-World Data (RWD) is typically observational in nature and relates to the ‘actual use’ of the device in the post-market setting (i.e., how users, healthcare professionals, and/or patients use the device in reality) during the routine use of the device in clinical practice. Real-world evidence (RWE) is evidence derived from the evaluation of RWD[footnoteRef:42], [footnoteRef:43].
RWD are data that describe patient characteristics (including treatment utilisation and outcomes) in routine clinical practice. RWE is evidence derived from the analysis of RWD. RWE Reflection paper - final version for publication
Uses of real-world evidence in a regulatory context (IMDRF meeting 2023)
RWD is distinct from data collected through clinical investigations. Clinical investigations, by their design, generally collect data through more controlled, structured, and systematic methods compared with RWD. Often the study population in a clinical investigation reflects a narrow sample of the overall population that would receive/use the device in routine clinical practice. Some examples of RWD include (list not exhaustive):
· data derived from hospital information systems (HIS) such as electronic health records (EHRs)[footnoteRef:44],
REGULATION (EU) 2025/327:
Preamble 7) “In health systems, personal electronic health data are usually gathered in electronic health records, which typically contain a natural person’s medical history, diagnoses and treatment, medications, allergies and vaccinations, as well as radiology images, laboratory results and other medical data, spread between different actors in the health system, such as general practitioners, hospitals, pharmacies or care services”.
Article 2 (j) ‘electronic health record’ or ‘EHR’ means a collection of electronic health data related to a natural person and collected in the health system, processed for the purpose of the provision of healthcare.
· data from registries (e.g. from device, patient or disease registries),
· device generated data (e.g., implantable devices, physiological monitoring devices),
· data from clinically annotated biobanks[footnoteRef:45], and
Note the importance of extensive and consistent annotations of samples; an overview of best practices is found in Sanderson-November M, Silver S, Hooker V, Schmelz M. Biorepository best practices for research and clinical investigations. Contemp Clin Trials. 2022 May;116:106572. doi:10.1016/j.cct.2021.106572. Epub 2021 Sep 25. PMID: 34583056; PMCID: PMC9275522.
· data gathered from other sources that can inform on health status, such as data from digital health technologies.
[bookmark: _Toc446499036][bookmark: _Ref168408918][bookmark: _Toc236912894]Clinical data generated and held by the manufacturer
[bookmark: _Hlk141803358][bookmark: _Hlk141803172]Available clinical data generated and held by the manufacturer needs to be identified and:
· made available to the evaluators (including external experts when applicable),
· all identified data sets should be documented, meaning adequately summarised to the extent that it can be critically reviewed by others, appraised, analysed, and referenced in the clinical evaluation report;
· information regarding to which version of the product/ model/ size/ settings that data pertain should be included.
[bookmark: _Ref168408935][bookmark: _Toc236912895][bookmark: _Toc446499037]Clinical data not held by the manufacturer
The manufacturer needs to identify publicly available clinical data in the literature that are needed for the clinical evaluation through planned and documented searches. Comprehensive searches are recommended, in particular for high-risk devices. A comprehensive search can be understood as a search that is not restricted to English language; where at least two electronic databases had been searched (such as MEDLINE or EMBASE); and at least one of the following search methods has been used to identify non-peer reviewed publications: searches for (i) conference abstracts, (ii) theses, (iii) registers; and (iv) contacts with experts in the field. The purpose of thorough and comprehensive literature searches is to avoid missing key studies and to minimize bias since a systematic review based only on published (or easily accessible) studies may have an exaggerated effect size. Examples of sources of data can be found in Appendix A5.
The following aspects should be considered for identification of data not held by the manufacturer (for more details, see Appendix A6):
· Searches should be:
· carried out based on a search protocol(s) that documents the planning of the search before execution), and
· documented to such degree that methods can be assessed critically, the results verified, and the search reproduced if necessary.
· The search protocol should:
· clearly state the purpose of the search (e.g., device under evaluation, equivalent device, similar device); and
· contain clear inclusion and exclusion criteria.
· The search report should:
· appropriately reflect results from search(es); and
· include information on any deviations from the search protocol.
· The search strategy should:
· be thorough and objective, i.e. should identify available relevant favourable and unfavourable data; and
· address all device sizes, variants, models and accessories and the same intended purpose.
Where a publication has been identified as relevant for inclusion, appropriate efforts should be made to access full-text publication. Where a full-text copy is not retrieved, justification should be provided, with due consideration to the overall identified clinical data available.
The literature search protocol, the literature search report, full list of retrieved and excluded articles (with reasons for exclusion) and full text copies of relevant available documents become part of the clinical evaluation documentation and, in turn, the technical documentation for the medical device, see section 12.1 for further guidance on the structure on the clinical evaluation documentation.
[bookmark: _Toc236912896]Data outside the definition of Article 2(48)
Data falling outside the definition of clinical data in Article 2(48) are not considered as clinical data for clinical evaluation purposes. Such data are often generated and analysed as part of the preclinical evaluation. Such data can be valuable for product development, including risk management activities or as support to clinical evaluation findings. It is not, however, sufficient to use only such data for conformity assessment with those GSPRs that the manufacturer has identified as requiring clinical data[footnoteRef:46].
Exception described in Section 7 for devices falling under Article 61(10)
Examples of data outside the definition of Article 2(48) include (list not exhaustive):
· data generated from non-clinical testing methods, for example, ex vivo studies and cadaveric studies, computer modelling and simulated use testing, including software-based models, 3D printed models, and other physical models (list not exhaustive);
· data from similar (non-equivalent) devices for a non-CE-marked device;
· data / patient information collected to train MDSW (see Appendix A4, e.g., CT-scan images collected to train diagnostic MDSW; and
· other studies and reports of other clinical experience for a non-CE-marked device that have not been published in scientific literature.
[bookmark: _Toc446499038][bookmark: _Toc236912897][bookmark: _Ref164155836][bookmark: _Ref164263146][bookmark: _Ref165303100]Appraisal of relevant clinical data (Stage 2)
[bookmark: _Toc446499039][bookmark: _Ref233794092][bookmark: _Toc236912898]General considerations
Appraisal involves the assessment of the clinical data identified in Stage 1 to determine the suitability of the data to demonstrate the safety and performance of the device.
Appraisal enables the manufacturer to understand the strengths and limitations of each data set.
[bookmark: _Toc446499040][bookmark: _Ref170995518][bookmark: _Ref233794028][bookmark: _Ref233794076][bookmark: _Toc236912899] Appraisal plan
To ensure systematic, rigorous, and unbiased appraisal of the data, the evaluators should set up an appraisal plan that describes the procedure and the criteria to be used for the appraisal.
The appraisal plan should be designed to be executed in line with relevant best practice guidance on critical appraisal, such as utilising validated critical appraisal tools that are appropriate to the data being appraised. In some cases, multiple tools and techniques may be needed to adequately appraise all the different types of quantitative and qualitative data identified in Stage 1.
When reviewing literature, there are many established, internationally recognised recommendations, tools, and resources on critical appraisal methodology, which can be referred to. Taking into account the nature, intended purpose and risks associated with the device in question, it may be appropriate to incorporate such resources into the appraisal plan. Examples of such resources include (non-exhaustive):
· Cochrane Methods Network and Cochrane Prognosis Methods Group tools
· GRADE (Grading of Recommendations, Assessment, Development, and Evaluations)
· IMDRF Clinical evaluation resources, such as IMDRF WG/N56FINAL:2019 (International Medical Device Regulators Forum)
· JBI Manual for Evidence Synthesis (Joanna Briggs Institute)
· EQUATOR network guidelines (Enhancing the quality and transparency of health research)
· AMSTAR (Assessing the Methodological Quality of Systematics Reviews)
· NOS (Newcastle-Ottawa Scale)
· CASP (Critical Appraisal Skills Programmes) checklists
Detailed overviews of commonly used appraisal and methodological quality assessment tools are available from academic sources[footnoteRef:47],[footnoteRef:48].
Zeng X, Zhang Y, Kwong JS, Zhang C, Li S, Sun F, Niu Y, Du L. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015 Feb;8(1):2-10. doi: 10.1111/jebm.12141. PMID: 25594108.
Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Mil Med Res. 2020 Feb 29;7(1):7. doi: 10.1186/s40779-020-00238-8. PMID: 32111253; PMCID: PMC7049186.
The appraisal plan typically includes:
· criteria for determining the scientific validity (including internal and external validity) of each data set
· criteria for determining the relevance to the clinical evaluation (relevance to the device and to the different aspects of its intended purpose) of each data set
· criteria for weighting the contribution of each data set to the overall clinical evaluation.
Each of these elements are discussed in detail in section 9.3 of this guidance.
The appraisal should be thorough and objective, i.e. it should identify and attribute adequate weighting to both favourable and unfavourable contents of each document.
The criteria adopted for the appraisal should reflect the nature, history and intended use of the device. They should be documented and justified on the basis of the SOTA, applying accepted scientific and technical standards.
The appraisal plan should be documented in the clinical evaluation plan, or it may be a standalone document which is referenced in the other clinical evaluation documents.
[bookmark: _Toc446499041][bookmark: _Ref233793990][bookmark: _Toc236912900]Conduct of the appraisal
To conduct the appraisal, the evaluators should:
· follow the pre-defined appraisal plan and apply its criteria consistently throughout the appraisal.
· base their appraisal on the full text of publications and of other documents (not abstracts or summaries), in order to review all the contents, the methodology employed, the reporting of results, the validity of conclusions drawn from the investigation or report, and evaluate any limitations and potential sources of error in the data.
· document the appraisal in the clinical evaluation report (or a referenced appraisal report) to the extent that it can be critically reviewed by others.
[bookmark: _Ref171518528]As discussed in section 9.3.2, when conducting the appraisal, it is important to consider the scientific validity of each report/publication. This encompasses both ‘internal validity’ and ‘external validity’. Internal validity examines whether the study design, conduct, analysis and conclusions adequately answer the research questions with accuracy and minimal bias 54. External validity examines whether internally valid findings produced from a dataset can be generalized to other populations, other settings and “real world” clinical practice [footnoteRef:49],[footnoteRef:50]. For example, an individual study may be well designed with high internal validity, but the study population may be limited to a small subset of the overall intended patient population, which may limit its external validity and limit the ability to generalise its findings. Internal and external validity may be interrelated, such as a needing a sufficiently large sample size to both minimize random errors and ensure generalisability.
European Commission, Directorate-General for Research and Innovation, Group of Chief Scientific Advisors, Scientific advice to European policy in a complex world, Publications Office, 2019, https://data.europa.eu/doi/10.2777/80320.
Cochrane Handbook for Systematic Reviews of Interventions
As discussed in section 9.3.2, the appropriateness and relevance of each study’s research questions to the issues that need to be addressed by the clinical evaluation (as discussed in Section 7) should then be considered.
As discussed in section 9.3.3, an appropriate weighting should then be applied to each data set.
It should be noted that for clinical data created and held by a manufacturer, the manufacturer will have access to a greater amount of information than for clinical data sourced from literature. For clinical data held by a manufacturer, the manufacturer should appraise the scientific validity, relevance and weighting of each data set based on the totality of information available to them and not just on any published information.
[bookmark: _Toc446499042][bookmark: _Toc236912901]Assessment of scientific validity of clinical data
Assessing the scientific validity of each data set will help the evaluator to determine the likelihood that:
· reported device performance outcomes and effects are reliable for clinical evaluation purposes
· device safety has been adequately assessed and reported
· the data source is appropriate for clinical evaluation purposes.
Low quality data sources may produce data with inaccuracies, which risk misinterpretation and may lead to erroneous findings and conclusions. However, these clinical data (e.g., data from individual case reports, data sourced from abstracts only, etc.) may play a non-pivotal, supportive role in the analysis for purposes such as:
· identifying new or emergent hazards or safety issues associated with the device,
· justifying the validity of surrogate endpoints (if surrogate endpoints are used),
· providing input for the planning of generation of additional clinical data.
The critical appraisal tools and resources discussed in Section 9.2 include detailed guidance on appraising the scientific validity of data from clinical research, and evaluators are encouraged to avail of these resources as appropriate. Examples of aspects that should be taken into consideration for appraising different sources of clinical data are detailed below. Many of the aspects described are relevant to multiple clinical data types and should be considered regardless of the clinical data source. For example, many aspects described under “Data from clinical investigations” are relevant for “Clinical studies reported in scientific literature” and vice versa.
For examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety, see Appendix A7.
1.1.1.1. [bookmark: _Ref164531769][bookmark: _Toc236912902]Data sourced from clinical investigations
In addition to established legal requirements, clinical investigations, as described in section 8.1.1, should comply with Good Clinical Practice (GCP) guidance, such as ISO 14155 or equivalent standards which are/were published at the time of study initiation. Failure to comply with GCP guidance may be an indicator of poor study quality and the study findings may not be valid.
As per art. 61(3) of MDR, it shall be taken duly into consideration whether the clinical investigation has been performed under Articles 62 to 80 of MDR, any acts adopted pursuant to Article 81, and Annex XV. For clinical investigations not performed under these articles or corresponding articles under the Directives, for example clinical investigations conducted outside EU or under Article 82 of MDR, a gap analysis should be performed as part of the appraisal to assess the degree to which the clinical investigation is concordant with the principles laid out in Articles 62 to 80 of MDR and relevant international standards. If gaps exist that may compromise the validity of the clinical investigation, then further studies in keeping with these principles may be needed.
The following should be considered when assessing the scientific validity of clinical investigations:
· Study type and design
The design of a clinical investigation is dependent on a number of factors such as the nature of the device under investigation, the stage of development of the device, the risks associated with the device, the mechanism of action of the device, the procedures associated with the device and the current standard of care for the condition in question. The random assignment of participants to one or more interventions in a controlled clinical investigation produces the highest quality of evidence.
The appropriateness of the study design to provide evidence of sufficient quality should be assessed. Please see Sections 11 and 13 for further details on the evidence which can be provided by pilot, pivotal or PMCF clinical investigations.
In relation to study conduct and monitoring, the methods used by the clinical investigation to limit the effect of bias (see ‘Limitations’ section) and confounding, and the reliability and effectiveness of these methods, should be assessed if available. Methods employed may include:
· randomisation
· blinding of participants, investigators, persons responsible for evaluating the outcome and/or persons responsible for analysing the results to the device, interventions, assessments or results in the clinical investigation
· the use of placebos, placebo procedures or other comparators as controls in the clinical investigation
· the use of stratification, minimisation or other techniques for preventing a baseline imbalance of prognostic factors
· the handling of medication or concomitant treatments in the study
· adequate of adverse event and device deficiency reporting. The ability of the clinical investigation to sufficiently detect safety signals should be assessed. All clinical investigations should have a monitoring plan that takes into account the characteristics of the clinical investigation, including objective(s) and methodology, and the degree of deviation of the intervention from normal clinical practice. Risk-based monitoring should be carried out on the basis of the risk assessment in the clinical investigation plan. Clinical investigations with higher levels of risk to participants should have a data safety and monitoring committee reviewing data as it emerges.
The consistency of the study conduct and analysis with the pre-specified design, hypothesis, and analysis plan should also be assessed.
· Limitations
The study should be assessed for the presence of bias. Bias comes in many forms (e.g., sampling bias, selection bias, response bias, observer bias) and a number of tools exist for assessing bias in a study. One method[footnoteRef:51] involves assessing if there is a low, medium or high risk of bias across domains such as:
Cochrane Risk of Bias tool (RoB 2)
· the randomisation methods employed, if applicable
· deviations from intended interventions
· missing outcome data
· measurement of outcomes
· selection of the reported result.
Other limitations of the study such as confounding influences, limited disclosure of data, etc. should also be assessed.
· Sample size and population
The study being appraised should be sufficiently powered to detect the effect(s) related to the outcomes of interest and details of the sample size calculation should be considered.
The adequacy of the inclusion and exclusion criteria employed by the study, as well as factors used in patient stratification (such as age, indication, severity of the condition, gender, other prognostic factors) should be assessed.
· Outcomes and reporting
· Endpoints. The adequacy and relevance of any endpoints used should be assessed. Good quality sources of evidence contribute to the evaluation of clinical benefit by assessing meaningful, measurable, patient-relevant clinical outcome(s)[footnoteRef:52]. Studies using endpoints which show direct clinical effects (such as morbidity, mortality or adverse events) are one source of this evidence. Studies using Patient Reported Outcome Measures (PROMs) may also be a source of this evidence, as they can provide qualitative evidence for the overall procedure. Studies using surrogate endpoints should only be considered as a good quality source of evidence following appropriate validation of the association of these endpoints with clinical outcomes.
Article 2(53) of MDR
The reliability and validation of any methods used for quantifying symptoms and outcomes should be assessed.
· Follow-up period. The adequacy of the study’s follow-up period to detect the outcomes under investigation should be assessed. Follow-up should also be at an adequate frequency to detect temporary side effects and complications (such as those related to wound healing).
· Statistical techniques employed. The use of statistical techniques such as imputation or extrapolation of data, how multiplicity was dealt with or how regression or sensitivity analyses have been conducted should be assessed. Methods of analysis (such as intention-to-treat or per protocol) should be explained and justified. Any formal hypothesis testing conducted on the clinical investigation data should be justified in their ability to exclude random error.
· Clinical investigations carried out by or on behalf of a manufacturer
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is expected that documentation relating to the design, ethical and regulatory approvals, conduct, results, and conclusions of the investigation needed for the clinical evaluation will be available for consideration, as appropriate. These may include:
· the clinical investigation plan
· clinical investigation modifications/amendments and the rationale for these changes
· case report forms, monitoring and audit records
· relevant ethics committee documentation
· documentation of relevant regulatory authority approvals, as applicable
· signed and dated clinical investigation report and its summary (for investigations that are terminated/ended)
· for investigations that are ongoing, the latest intermediate report available and the latest collation of serious adverse events, device deficiencies, and protocol deviations
· the latest reviews and conclusions from independent monitoring committees, such as data safety monitoring boards (DSMB), as applicable
· for clinical investigations conducted outside of the EU, an appraisal of whether the results are transferable to the European population.
The clinical investigation plan sets out how the study was intended to be conducted. It contains important information about the study design such as the selection and assignment of participants to treatment, blinding (of participants and/or investigators) and measurement of responses to treatment, which may be important sources of bias that can be assessed and possibly discounted when attempting to determine the actual performance of the device. In addition, the clinical investigation plan sets out the intended participant follow-up, approaches to statistical analyses, and methods for recording outcomes, which may impact the quality, completeness and validity of results obtained for performance and safety outcomes.
By including the clinical investigation plan, its amendments/modifications, related approvals of ethics committees/competent authorities and the clinical investigation reports in their review, evaluators will be able to assess the extent to which the investigation was conducted as planned and, where deviations from the original plan have occurred, the impact those deviations had on the robustness and reliability of the data generated and the conclusions that can be drawn from the investigation about the performance and safety of the device.
Evaluators should confirm that compliance with applicable ethical standards, medical device standards (for example EN ISO 14155 or comparable standards) and applicable regulatory requirements has been demonstrated.
The evaluators should verify whether clinical investigations have been defined in such a way as to confirm or refute the manufacturer's claims for the device; and whether these investigations include an adequate number of observations to guarantee the scientific validity of the conclusions.
· Clinical investigations sourced from scientific literature
When reviewing data from clinical investigations in scientific literature, many of the aforementioned principles in this section will apply and should be reviewed. Critical appraisal and assessment tools, such as those referenced in section 9.2, are a valuable resource when reviewing scientific literature, and these should be utilised as appropriate when evaluating and appraising scientific literature.
When reviewing scientific literature, evaluators will typically only have access to the published study report and appendices. As such, in addition to the aforementioned aspects, evaluators should consider the following aspects regarding the report[footnoteRef:53]:
Where “adequacy” is mentioned in the following points, it may not be sufficient or appropriate to appraise adequacy on a binary adequate/not adequate scale and further elaboration may be required. The degree of adequacy may impact the weighting discussed in Section 9.3.3.
• adequacy of disclosure of methods used,
• adequacy of disclosure of data generated, where applicable. This includes the:
- completeness of the reporting of adverse events, device deficiencies, and outcomes
- disclosure of all the results the study was originally designed to generate.
• validity of interpretation of data and conclusions drawn by the authors (i.e., do the conclusions align with the results)
• adequacy of acknowledgement of limitations by report authors.
Possible conflicts of interest and affiliations, disclosed or otherwise, of the authors, sponsors/research institutions, and study funders should be taken into consideration.
It is recognised that, where manufacturers source clinical data from scientific literature, the documentation readily available to the manufacturer for inclusion in the clinical evaluation is likely to be no more than the published paper itself. In cases where substantial amounts of data are not available for evaluation, the validity of the study may be negatively impacted.
While a publication in a peer-reviewed scientific journal is generally indicative of a certain level of scientific quality and clinical relevance, such publication is not considered an acceptable reason for bypassing or reducing appraisal activities.
· [bookmark: _Ref164068470][bookmark: _Ref164531771]Clinical investigations based outside of the EU
Clinical data collected from a clinical investigation only conducted outside of the EU should be evaluated as clinical data for the purposes of conformity assessment under MDR. When evaluating these data, the following characteristics need to be assessed in addition to those described elsewhere in this stage, to determine the quality, scientific validity, and relevance of the data:
· the clinical investigation was conducted in line with the legal, ethical, and regulatory requirements applicable to that jurisdiction.
· it has been demonstrated that the clinical investigation has been designed and conducted in conformity with appropriate international good clinical practice standards, such as ISO 14155 or equivalent standards which are/were published at the time of study initiation, and in line with the Declaration of Helsinki.
the clinical investigation was conducted in keeping with the principles of Chapter VI and Annex XV of MDR, in particular:
the rights, safety and well-being of subjects were protected
· appropriate monitoring of the clinical investigation was conducted
· adverse events were appropriately handled
· data was handled in an appropriate manner
· informed consent was obtained from subjects
· vulnerable populations were appropriately protected.
· the clinical investigation was conducted in line with applicable device-specific international standards and consensus expert guidance recommendations (if any),
· the data can be validated through appropriate means, such as review of the clinical investigation documentation (CIP, IB, CIR, case report forms etc.).
If clinical data only partially meets the above criteria, the data may be given reduced “weight” as part of the appraisal process (see Section 9.3.3). Clinical data that is appraised to be poor quality will unlikely, on its own, to be sufficient to demonstrate conformity with the GSPRs and will need to be supported by additional clinical data.
1.1.1.2. [bookmark: _Toc236912903] Data from studies other than clinical investigations
Studies other than clinical investigations may share many common aspects with clinical investigations, and therefore, many of the aspects outlined in section 9.3.1.1 are relevant when appraising these studies. In particular, attention should be drawn to the following aspects:
• what types of biases exist and how are these minimised?
• how were confounders identified and controlled?
• were the sourced data obtained from appropriate clinical sites?
• how representative is the study data with respect to the lifecycle of the device and its use in the clinical setting?
• is there a clear patient flow presented in the study report?
• were valid quality control methods used to obtain the reported data?
• are the study results consistent with other scientific studies?
• is the study report's conclusion consistent with the data presented in the results?
1.1.1.3. [bookmark: _Toc236912904] Data from reports on other clinical experience of the device
As discussed in section 8.1.3, reports published in peer reviewed scientific literature from "other clinical experience" of a device may be collected from a heterogenous range of sources. As a result, the scientific validity of such reports may vary considerably, and the peer review process alone may not provide adequate assurances of quality. An assessment of the scientific validity of each report should be undertaken. Many of the aspects discussed in Section 9.2 and Sections 9.3.1.1 and 9.3.1.2 may be relevant to the assessment of these reports and, if relevant, should be considered.
1.1.1.4. [bookmark: _Toc236912905]Data from clinically relevant information generated from the PMS system
The clinical evaluation shall be updated throughout the lifecycle of the device with clinical data obtained from implementation of the manufacturer’s post-market surveillance (PMS) plan and post-marketing clinical follow up (PMCF) plan.
PMS and PMCF findings should be assessed with consideration of the following aspects:
· the time periods considered
· the populations studied, including clinical and demographic features
· the objectives of the plan.
Conclusions reached on this data should be assessed with regards to its relevance for the intended target population of the device in question.
Should the source of the data in the report deviate from the respective plan, this deviation should be explained. Data presented with a significant deviation from the respective plan may need to be treated with caution.
PMCF studies
The following should be considered when appraising the data from PMCF studies (aspects may be relevant to other PMCF):
· what were the procedures used for retrieving information about outcomes?
· what is the population in the study? How representative and complete is the population in the study in relation to the intended target population of the device in question?
· how complete is the data collection in the study? Was there active follow-up of participants in the study? How many participants have been lost to follow-up, have these losses been appropriately explained and how are these participants considered in any analysis undertaken?
· how has data quality in the study been considered?
· how appropriate is follow-up duration for assessment of potential device issue? Note that PMCF studies with robust follow-up can produce the highest quality post-market clinically relevant information.
· was the study and any data analysis undertaken based on a pre-specified plan? Was a reasonable justification for the approaches taken in place prior to the study taking place?
· were any legal obligations for the study followed?
Please see Section 13 for further information on PMCF studies.
Registries
For registries, the activity, coverage, completeness and accuracy of the data should be assessed. To do this, the structures and methods used by the registry and the suitability of the data source should be considered. An important consideration is if the source of the information is a registry-based study, a device registry, or a patient registry. A registry-based study is an investigation of a research question or hypothesis using data from an existing registry. Registry-based studies may have a more restricted scope of data collection (which will be defined by the research question and objective) than the available data set in a device registry, and the ability of the registry-based study to collect all relevant data should be carefully considered. Data from device registries, case series, retrospective analyses of patient dossiers, and other use data can be useful sources of information when conducting an evaluation of the real-world use of a device. However, care is needed when using these sources, as the retrieval of information about outcomes may be incomplete and unreliable.
Surveys
The design of surveys should be assessed with well executed, statistically valid surveys that have clear and focused objectives and endpoints considered to produce the most robust evidence. High quality surveys should collect information at a case specific level (as opposed to general use of a device) and provide specific information on the safety and performance of the device, rather than on general usability[footnoteRef:54].
Planning, designing and implementing high quality (Level 4) post market clinical follow up surveys. Journal of Medical Device Regulation, 2023, 20(4), 31-44
Reactive PMS, vigilance, and other post-market data
Evaluation of reactive PMS, vigilance, and other post-market data should consider that under-reporting or lack of reporting of side-effects or complications by users is common. Therefore, PMS and vigilance systems do not typically deliver adequate information about the true frequency of expected undesirable side-effects and complications[footnoteRef:55]. Such systems are most useful for identification of unexpected risks. Reports of clinical experience that are not adequately supported by data, such as anecdotal accounts of experiences or opinions, may contribute to the evaluation (e.g. for the identification of unexpected risks) but should not be used as proof of adequate clinical performance and clinical safety of the device.
Systematic scientific data are needed for such purposes, e.g., data collected from adequately designed registries and PMCF studies
[bookmark: _Toc446499043][bookmark: _Toc236912906]Assessment of the relevance of a data set for the clinical evaluation
Assessing the relevance of a data set helps the evaluator to determine whether the findings and conclusions in the data set are:
· relevant and applicable to the device and its indications,
· representative of the intended population per the device’s intended use, and
· representative of the ‘real-world’ / expected use of the device in standard clinical practice, per the device’s intended use.
Evaluators may use validated critical appraisal tools and resources appropriate to the data set under appraisal, as described in section 9.2, which should aid in determining relevance. Table 1 shows aspects that should be included when determining if, and in what respect, data are relevant to the clinical evaluation of the device in question. For data originating outside the EU, evaluators should ensure it has been justified that the data is relevant and applicable to the EU population and EU standard clinical practice and is representative of the intended normal conditions of use of the device in the target patient population.
Table 1. Aspects to Determine the Relevance of a Data Set
Description
Examples
To what extent are the data generated representative of the device under evaluation?
· device under evaluation
· equivalent device (per MDR, see MDCG 2020-5)
· other devices and therapeutic alternatives
· data concerning the medical conditions that are managed with the device
What aspects relating to the device’s safety and performance are covered?
· performance data
· safety data
· claims
· identification of hazards
· estimation and management of risks
· determination and justification of criteria for the evaluation of the risk-benefit relationship
· determination and justification of criteria for the evaluation of acceptability of undesirable side-effects
· justification of the validity of surrogate endpoints
Are the data relevant to the intended purpose of the device or to claims about the device?
· representative of the entire intended purpose with all patient populations and all claims foreseen for the device under evaluation
· concerns specific models/ sizes/ settings, or concerns specific aspects of the intended purpose or of claims
· does not concern the intended purpose or claims
Are the data relevant to a specific:
· model, size, or setting of the device?
· smallest / intermediate / largest size
· lowest / intermediate / highest dose
· etc.
· user group?
· specialists
· general practitioners
· nurses
· adult healthy lay persons
· disabled persons
· children
· etc.
· indication (if applicable)?
· migraine prophylaxis
· treatment of acute migraine
· rehabilitation after stroke
· etc.
· age group?
· pre-term infants / neonates / children / adolescents / adults / old age
· sex?
· female/ male
· type and severity of the medical condition?
· early / late stage
· mild / intermediate / serious form
· acute / chronic phase
· etc.
· duration?
· duration of application or use
· number of repeat exposures
· duration of follow-up
[bookmark: _Toc446499044]
[bookmark: _Toc236912907]How to weight the contribution of each data set
The weighting of data is necessary to ensure that high-quality and relevant data is prioritised and given greater weight compared to data sources of lower quality or relevance.
Typically, clinical data generated through a well-designed and monitored randomized controlled clinical investigation (also called randomised controlled trial), conducted with the device under evaluation in its intended purpose, with patients and users that are representative of the target population should receive the highest weighting. It is acknowledged that randomized clinical investigations may not always be feasible and/or appropriate and the use of alternative study designs may provide relevant clinical information of adequate weighting, provided that studies are otherwise well-designed, well-conducted, and relevant to the device and its target population.
Clinical evaluators should strictly follow pre-defined criteria when weighting the data set. Due to the diversity of medical devices, there is no single method for weighting clinical data. A suggested method would be to identify criteria which would adequately allow appraisal of each data set’s scientific validity (as outlined in section 9.3.1) and relevance (as outlined in section 9.3.2). Each data set should then be graded based on these criteria, preferably in an outcome-specific manner by using well-established criteria to assess the quality of evidence (for example, by using the GRADE framework[footnoteRef:56]). Then, each data set should be weighted reflecting its appraisal grade.
https://www.gradeworkinggroup.org/
The following is an example of a weighting system which may be employed to assess clinical data sourced from clinical investigations. Where clinical data come from other sources, alternative criteria may be used. Manufacturers may employ a quantitative approach (i.e. 1=not sufficient, 2=partially sufficient, 3=sufficient) or qualitative approach (i.e. acceptable/not acceptable) to grade the components of each criterion.
For quantitative approaches, grading will result in an overall score and thresholds should be defined for the evaluation of the quality of the data source. Care should be taken to prevent less significant aspects of a clinical investigation given equal weight to more significant aspects. For qualitative approaches, a summary of the acceptability of the considered aspects of a clinical investigation will be provided.
Scientific validity criteria
Criteria
Description
Grade
System be decided by manufacturer (either quantitative or qualitative)
Study design and conduct
Adequacy of study design
Adequacy of study endpoints
Adequacy of the assessment of adverse events
Adequacy of study follow up periods
Limitations
Sufficiency of measures taken to limit the risk of bias (or other limitations unrelated to bias)
Study size
Power of the study to detect the relevant outcomes under consideration
Outcomes and reporting
Adequacy and relevance of:
· Methods used to quantify outcomes
· Methods for data collection, transfer, and processing
· Statistical techniques employed
· Disclosure of data
· Justification of the validity of conclusions drawn
Quality Assurance
Conduct in keeping with Good Clinical Practice guidance
Appropriateness of monitoring undertaken by the study
Study documentation
Availability and completeness of study documentation
Relevance criteria
Criteria
Description
Grade
Device
Were the data generated from the device under evaluation?
Appropriate Device Use
Was the device used (e.g., methods of deployment, application, etc.) according to the manufacturer’s IFU?
Intended population
Were the data generated from the intended population of the device/representative of the expected use of the device in clinical practice?
It should be noted that the above is presented as an example of a weighting system which may be used. Different approaches to weighting clinical data exist (such as the GRADE framework, which uses well-established criteria to assess the quality of evidence) and alternative approaches are acceptable.
Principles on when the evaluator should consider rejecting individual data sets should be created. When rejecting data sets, the evaluators should document the reasons (both for studies and reports that have been generated and are held by the manufacturer, and for other documents identified during Stage 1).
Following the weighting process for each individual data source, the clinical data sources for the device under evaluation may be ranked in relation to the contribution of each data set to the assessment of the device's safety and performance. The following is a suggested hierarchy of clinical data sources resulting from the appraisal process, ranked from strongest to weakest (some variations may apply to this depending on the device in question and the nature of individual data sources):
Rank
Clinical data source
1
Results of high-quality clinical investigations covering all device variations, indications, patient populations, duration of treatment effects, etc.
2
Results of high-quality clinical investigations with some gaps
3
Outcomes from high quality clinical data collection systems such as registries
4
Outcomes from studies with methodological flaws but where data can still be quantified and acceptability justified
5
Equivalence data
6
Curated complaints and vigilance data
7
Proactive PMS data, such as that derived from surveys
8
Individual case reports on the subject device
[bookmark: _Toc446499045][bookmark: _Ref163813563][bookmark: _Ref164155845][bookmark: _Ref164263164][bookmark: _Ref165303113][bookmark: _Toc172294355][bookmark: _Ref233292132]
[bookmark: _Toc236912908]Analysis of relevant clinical data (Stage 3)
The goal of this stage is to analyse all relevant clinical data to reach conclusions about the overall safety and clinical performance of the device including its clinical benefits[footnoteRef:57]. This enables evaluators to determine if the clinical data provide sufficient clinical evidence to confirm conformity with each of the relevant GSPRs[footnoteRef:58] outlined in the CEP, taking into account the generally acknowledged SOTA (see Stage 0).
MDR Annex XIV, Part A, section 1(e)
See Appendix A9
In this stage, the evaluators should:
· comprehensively analyse all relevant clinical data (see 10.1 for further guidance),
· assess whether the clinical data provide sufficient clinical evidence to confirm conformity with relevant GSPRs[footnoteRef:59] (see 10.2),
Per MDR Article 61(1)
· determine if the generation of new or additional clinical data is needed (see 10.3).
The conclusions of the analysis should be documented in the CER (Stage 5).
All clinical data included for analysis should first be appraised in accordance with Stage 2. The analysis should give due consideration to this appraisal when considering the value of each dataset in terms of its contribution to the clinical evidence of the device. This is true for both favourable and unfavourable data. The appraisal assesses the suitability of the clinical data for providing clinical evidence with respect to the device’s safety and clinical performance; however, determining whether the clinical data confirm conformity with the relevant GSPR[footnoteRef:60] will depend on the analysis of the data.
Including the evaluation of undesirable side-effects and acceptability of the benefit-risk ratio, see 10.2
Note: where analysis of the clinical data has identified new undesirable side effects or risks that may affect the acceptability of the benefit-risk ratio, the manufacturer should take appropriate actions to address these, including appropriate risk control measures to reduce risks as far as possible within the manufacturer’s risk management system. A summary of these actions should be included in the clinical evaluation where relevant.
[bookmark: _Toc236912909]Comprehensive analysis of all relevant clinical data
The analysis must be thorough and objective and must take into account both favourable and unfavourable data. Its depth and extent must be proportionate and appropriate to relevant device characteristics including the nature, classification, intended purpose, and risks of the device in question, as well as to the manufacturer's claims in respect of the device[footnoteRef:61].
per MDR Annex XIV Part A, section 2
The analysis should use justified, methodologically sound methods to reach conclusions on the safety and clinical performance of the device, including its clinical benefits.
Clinical data can be quantitative and/or qualitative, and appropriate analysis methods should be used depending on the type of data. In general, it is anticipated that most clinical data will be quantitative; however, it is acknowledged that qualitative data may be analysed in some scenarios. Sole or predominant reliance on qualitative data should be scientifically justified.
Pivotal data may not necessarily come from a single source and may result from an aggregate of clinical data. When analysing multiple sources of clinical data, evaluators should look for consistency of findings across the clinical datasets. If multiple data sources report similar clinical outcomes, confidence in conclusions from the data increases. If different results or discrepancies are observed across the data or between data sets, further analysis should be made to determine the reason for such differences. All identified available clinical data should be considered and included, taking into account the quality and relevance of the data, as appraised during Stage 2. Where relevant, a rationale should be given for the exclusion of clinical data from its analysis in the clinical evaluation.
The analysis should take into account at least the following:
· all devices covered by the clinical evaluation, including models, sizes, variants, accessories, and configurations as appropriate, and all aspects of their intended purpose.
The SOTA and the level of clinical evidence necessary, per Appendix A10, including
· clinical outcome parameters as per CEP
· parameters, including acceptance criteria where applicable[footnoteRef:62], to be used to determine the benefit-risk ratio as per CEP
See section 7 for further information
· the appraisal of each clinical data set per Stage 2,
· risks to patients, users or other persons associated with the use of the device,
· the findings from clinical data with respect to the safety, clinical performance, and clinical benefits of the device.
[bookmark: _Ref233801997][bookmark: _Ref233802075][bookmark: _Ref233802120][bookmark: _Toc236912910]Clinical evidence for conformity with relevant GSPRs
The analysis should be evaluated against the specified level of clinical evidence necessary, described in Stage 0 and in Appendix A10.
With due regard to the specified level of clinical evidence necessary, the manufacturer should determine whether the relevant clinical data provide sufficient clinical evidence to form a basis for the confirmation of conformity with the relevant GSPRs requiring clinical data[footnoteRef:63] under the normal conditions of the intended use of the device, in relation to the
As identified in the CEP
· device safety and performance,
· evaluation of undesirable side-effects, and
· evaluation of the acceptability of the benefit-risk ratio for the device,
The manufacturer should then determine whether the generation of new or additional clinical data is required, as described in 10.3.
[bookmark: _Toc236912911]Determining the requirement for new or additional clinical data
To determine if the generation of additional clinical data is required[footnoteRef:64], the evaluators should identify and describe any relevant gaps in available clinical data, including any gaps that may affect:
As outlined in MDR Annex XIV Part A, section 1(d)
· the consideration of specifics of the interaction between the device and the human body
· the comprehensiveness of the available clinical data, taking into account:
· the range of devices covered by the clinical evaluation, including models, sizes, variants, accessories, and configurations as appropriate
· the entire range of conditions of use and of the intended purpose
· the number of patients that have been exposed to the device to date
· the adequacy of patient follow-up data
· the ability to identify and evaluate hazards and undesirable side-effects throughout the device expected lifetime
· the evaluation of the benefit-risk ratio for the device.
Additional clinical data should be generated to address relevant gaps. See Stage 4 (see Section 11) for more information.
[bookmark: _Ref164263177][bookmark: _Toc172294358]
[bookmark: _Toc236912912]Generation of new or additional clinical data (Stage 4)
During the clinical evaluation and throughout the lifecycle of the device, outstanding issues may be identified that need to be addressed through the generation of new or additional clinical data. These issues may become apparent in the pre-market setting, or they may emerge in the post-market setting where new information - related to the device in question, similar or equivalent devices, the SOTA, or normal clinical practice - identifies issues that had not previously emerged or were not identifiable in the pre-market setting.
Depending on the individual scenario, new or additional clinical data may need to be generated or collected in the pre-market and/or post-market settings. The methods chosen need to be duly justified, and where applicable, new clinical data should be generated in line with relevant standards (e.g., ISO 14155), common specifications, appropriate GCP guidance (e.g., ICH guidance for studies of both devices and medicinal products), and/or internationally recognised consensus guidance and the relevant SOTA. Once generated, all new and additional clinical data should undergo appraisal and analysis in line with Stage 2 (see Section 9) and Stage 3 (see Section 10) of this guidance.
[bookmark: _Ref171001626][bookmark: _Toc236912913][bookmark: _Hlk167799782][bookmark: _Toc158731012]Pilot and pivotal pre-market clinical investigations
While pre-market clinical investigations are mandatory for certain high-risk medical devices (see MDCG 2023-7), it may be necessary for a manufacturer to perform pilot and/or pivotal clinical investigations for devices of any risk class as part of their clinical development plan, for the purposes of generating new or additional clinical data. MDCG 2021-6 gives further detailed guidance regarding the planning and conduct of clinical investigations.
Of note, the developmental stage of a clinical investigation is an important characteristic that should be specified and understood during clinical development and evaluation planning; however, for clinical evaluation purposes, the scientific validity of the data produced by the study is more relevant than the developmental stage it has been assigned. For example, a clinical investigation may be planned as a pivotal investigation, however the results may be inconclusive or may fail to statistically confirm or reject the study hypothesis, and thus the clinical investigation may not have produced pivotal data. In such cases, it may be necessary to generate additional clinical data which may provide sufficient clinical evidence when all clinical data sources are evaluated together.
[bookmark: _Toc236912914]Pilot (early-stage, pre-market) clinical investigations
Generally, pilot clinical investigations are exploratory in nature and are conducted early in the clinical development of a device.[footnoteRef:65] For high-risk medical devices, data generated in pilot clinical investigations generally do not provide sufficient clinical evidence on their own, and additional confirmatory clinical data (e.g., from pivotal clinical investigations) may be required for the purposes of conformity assessment.
For further information on pilot clinical investigations, please refer to MDCG 2021-6 question 8
Relevant data from pilot clinical investigations should be included in the CER, and their applicability to the current design of the device undergoing conformity assessment should be justified. This is particularly relevant where the device has undergone changes to its design or manufacturing process between the pilot clinical investigation and conformity assessment.
[bookmark: _Toc236912915]Pivotal (confirmatory, pre-market) clinical investigations
In later stages of a device’s pre-market clinical development, one or more pivotal, confirmatory clinical investigations may be conducted to provide the clinical data necessary to confirm the safety and clinical performance of a device. Typically, these clinical investigations use appropriate endpoints, outcome measures, and statistical methods (including the enrolment of a statistically justified number of human subjects) to test defined statistical hypotheses regarding the device’s safety and clinical performance. They are generally larger in scale than pilot clinical investigations and may involve multiple investigational sites to enrol the number of human subjects needed for meaningful statistical analysis. For certain low risk devices, well-designed small scale clinical investigations could potentially provide sufficient clinical evidence for conformity assessment, depending on the relevant aspects and considerations outlined in Appendix A10 as they relate to the device.
Where feasible and appropriate, pivotal clinical investigations should be designed to include a concurrent control arm (e.g. comparator, placebo, sham, etc.), with appropriate randomisation and blinding (e.g., single-blind or double-blind randomised control trials). However, other methods may be acceptable (e.g., observational studies such as case-control and cohort studies, cross-over studies, studies comparing the device with historical controls), provided they are methodologically sound and well designed with due consideration to potential biases and confounders, and with adequate justification for how the clinical investigation can be reasonably expected to provide sufficient clinical evidence (alone or in conjunction with other clinical data).
[bookmark: _Ref433562252][bookmark: _Toc446499049][bookmark: _Ref164263194][bookmark: _Ref165986843][bookmark: _Toc236912916]The clinical evaluation report (Stage 5)
The purpose of the clinical evaluation report is to document the results of the clinical evaluation and the clinical evidence on which it is based. The CER shall be part of the technical documentation for the device in question to support the assessment of the conformity of the device with relevant GSPRs.
The clinical evaluation report should be a standalone document and contain sufficient information to be read and understood by an independent party (e.g. regulatory authority or notified body). Therefore, it should provide sufficient information (summarising key information where full details are available in other documents) for understanding the search criteria and methods used for study selection, appraisal, analysis and syntheses of data adopted by the evaluators, the data that are available, all assumptions made and all conclusions reached.
The contents of the clinical evaluation report shall be cross-referenced to the relevant documents that support them. It should be clear which statements are substantiated by which data, and which reflect the conclusions or opinions of the evaluators. The report should include references to literature-based data, titles and clinical investigation identification codes (if relevant and available), any clinical investigation reports, with cross-references to the location in the manufacturer’s technical documentation.
The amount of information may differ according to the history of the device or technology. Where a new device or technology has been developed, it is recommended to clearly state in the CER where in the development process all clinical data have been generated.
An example of the clinical evaluation report format is provided in Appendix A11.
It is important that the CER reflects the results of the different stages of the clinical evaluation:
Stage 0, planning and scope of the clinical evaluation:
summarises the key information necessary to understand the context of the clinical evaluation, including which products/ models/ sizes/ settings are covered by the clinical evaluation and CER, the technology on which the medical device is based, the conditions of use and the intended purpose of the device, the sources of the clinical evidence
documents any claims made about the device’s clinical performance, including clinical benefit, or clinical safety
describes the state of art or summarises key elements if its full description is reported in the CEP or in a separate document
if claimed, describes how the equivalence to another device is demonstrated or references this, if contained in a separate document.
Stage 1, identification of available clinical data
provides a summary of the literature search strategy and study selection criteria applied for retrieval of information and its results
references to the detailed literature search protocol and report in the CEP or in a separate document
summarises the relevant clinical data sets (i.e. methods, results, conclusions) that have been identified.
Stage 2, appraisal of all relevant clinical data:
provides reference to the relevant CEP section or separate document where the methods to appraise all relevant clinical data are to be found
summarises the pertinent data sets (methods, results, conclusions of the authors); evaluates the scientific validity of the relevant clinical data sets (including internal and external validity), their relevance for the evaluation, the weighting attributed to the evidence, and any identified limitations
· presents justifications for rejecting certain data or documents.
Stage 3, analysis of all relevant clinical data:
explains if and how the referenced information constitute sufficient clinical evidence for demonstration of the clinical performance and clinical safety of the device under evaluation. This may include reference to clinical data requirements from applicable harmonised standards or common specifications
· explains whether there are adequate data for all aspects of the intended purpose and for all products/ models/ sizes/ settings covered by the clinical evaluation
describes the benefits and risks of the device (their nature, probability, extent, duration and frequency)
explains the acceptability of the benefit-risk ratio according to the SOTA in the medical fields concerned, with reference to applicable standards, common specifications and guidance documents, available medical alternatives, and the analysis and conclusions of the evaluators on fulfilment of all GSPRs pertaining to clinical properties of the device (see Appendix A9)
analyses if there is consistency between the clinical data, the information materials supplied by the manufacturer and the risk management documentation for the device under evaluation; whether there is consistency between these documents and the SOTA
· identifies any gaps and discrepancies
identifies residual risks and uncertainties or unanswered questions (such as rare complications, uncertainties regarding medium- and long-term performance, safety under wide-spread use) that should be further evaluated during PMS and in PMCF activities.
The evaluators should check the clinical evaluation report, provide verification that it includes an accurate statement of their analysis and opinions, and sign the report. Evaluators should provide their CV as an attachment to the CER.
Note that per article 61(2), the manufacturer shall give due consideration to the views expressed by the expert panel, and such consideration shall be documented in the clinical evaluation report.
Suggestions for aspects that should be checked for the release of a clinical evaluation report are summarised in Appendix A12.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
[bookmark: _Toc236912917]Clinical evaluation documentation
Typically, the clinical evaluation documentation includes:
· CEP, including CDP (mandatory)
· if not in the CEP, literature search protocol for SOTA and for the identification of clinical data, respectively
· if not in the CEP, the appraisal plan
· if not in the CEP, the analysis plan
· CER (mandatory document)
· if not in the CER, the literature search reports, including the full list of retrieved articles and full list of excluded articles with reasons for exclusion
· if not in the CER, the appraisal report
· if not in the CEP or CER, the SOTA description (see Appendix A1)
· if not in the CEP or CER, the full demonstration of equivalence, where relevant
· full text copies of relevant documents available
· for completed clinical investigations, the clinical investigation plan, report and its summary
· for ongoing clinical investigations, the clinical investigation plan and, if available, interim reports
· clinical investigations plan and report, where available
· evaluators’ curriculum vitae.
Note that all clinical evaluation documents should be dated and version controlled.
[bookmark: _Toc236912918][bookmark: _Ref163814734][bookmark: _Ref164263227]Post Market Clinical Follow-Up
Once placed on the market, the clinical evaluation should be updated throughout the device’s lifecycle by means of the continuous process of PMCF[footnoteRef:66]. When conducting PMCF, the manufacturer must proactively collect and evaluate clinical data from the use of the device in the post-market setting, with the aims of confirming the device’s safety and performance throughout its expected lifetime, ensuring the continued acceptability of benefit-risk ratio, detecting previously unknown side-effects, new or emerging risks related to use of the device, monitoring the identified side-effects and contraindications as well as verifying that the intended purpose is correct, by identifying possible systematic misuse or off-label use of the device[footnoteRef:67]. The manufacturer’s methods for achieving these aims must be laid down in a PMCF plan[footnoteRef:68]. The PMCF must be appropriately addressed in the manufacturer’s QMS[footnoteRef:69].
In accordance with MDR Article 61(11) and Annex XIV Part B.
Annex XIV, Part B
See MDCG 2020-7
Article 10(9)(f) of MDR
Clinical data that are collected through PMCF should be appraised and analysed in line with sections 9 and 10 of this guidance document, as part of PMCF evaluation of the device. The PMCF evaluation must be documented and regularly updated in a PMCF evaluation report[footnoteRef:70]. The conclusions of the PMCF evaluation report must be taken into account in the clinical evaluation as well as in the risk management for the device. If, through the PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer must implement them accordingly[footnoteRef:71]. Please refer to MDCG 2020-7 and MDCG 2020-8 for guidance on the PMCF plan and PMCF evaluation report, respectively.
See MDCG 2020-8. See section 14 of this document for further guidance.
Per Annex XIV, Part B, section 8
When developing a PMCF plan, the manufacturer should consider:
· the characteristics of the device in question, such as the invasiveness, duration of use, overall risk, residual risks, etc., and
· the conclusions of the clinical evaluation analysis stage, with particular attention to any uncertainties or limitations in clinical data that require further evaluation in the post-market setting.
For example, while the clinical evaluation may conclude that the clinical data provide sufficient clinical evidence to place the device on the market, there may be certain aspects where additional clinical data need to be collected in the post-market setting to confirm its continued safety and performance throughout its expected lifetime. Where pre-market clinical data may be limited with respect to certain aspects such as rare complications, long-term performance, safety under wide-spread use, etc., the PMCF should be designed to appropriately address these limitations. PMCF studies including PMCF clinical investigations may be indicated.
MDR provides for the possibility that the manufacturer justifies why PMCF is “not applicable”[footnoteRef:72]. The circumstances or criteria when a manufacturer may justify that a PMCF is not applicable are not specified in MDR. Note that in this context “not applicable” should be interpreted as “not relevant” or “not necessary” in the referenced MDR provisions. Note also that such non-applicability concerns all PMCF activities, including but not limited to PMCF studies. Considering the legal requirement for PMCF[footnoteRef:73], such non applicability should be limited to exceptional circumstances, and should be duly justified on a case-by-case basis. The justification should include clear rationale and explanation as to how, in the absence of PMCF, the safety and clinical performance will be confirmed throughout the expected lifetime of the device, the continued acceptability of identified risks will be ensured, and emerging risks will be detected.
MDR Annex II, Section 6.1 (d); Annex III, Section 1.1 (b), last indent; Annex VII, Section 4.5.5, last indent
MDR Article 61(11) and Annex XIV Part B
13.1 [bookmark: _Toc236912919]PMCF studies
Certain devices (e.g., high-risk devices, implantable devices, devices containing certain substances[footnoteRef:74], devices intended for long term use[footnoteRef:75]) may require long-term follow-up studies in the post-market setting to assess the device’s long-term clinical performance and to identify any potential long-term safety concerns. These PMCF studies include but are not limited to PMCF investigations (see Section 13.2). PMCF studies should be designed to effectively monitor the long-term follow-up of patients exposed to the device, to confirm the safety and clinical performance of the device throughout its expected lifetime. Long-term follow-up is especially important where the benefits or risks associated with a device may manifest slowly over an extended period.
Such as substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), substances having endocrine-disrupting properties (ED), medicinal substances, substances derived from human blood or human plasma, any tissues or cells of human or animal origin or their derivatives
Per Annex VIII section 1.3
Where feasible for PMCF studies, for the duration of recruitment in a study site, the manufacturer should plan to enrol a representative proportion of patients exposed to the device in that site. This is particularly important for devices that carry significant risks (i.e. high residual risks or risks of causing serious adverse events).
In addition to collecting objective clinical data reflecting safety and performance, PMCF studies may also capture, as secondary endpoints, real-world usability data from the user/healthcare professional perspective.
PMCF studies may be considered based on the following (not-exhaustive list):
· Long-term safety and/or clinical performance
PMCF studies may be designed to identify and further assess issues relating to a device’s long-term safety and clinical performance throughout its expected lifetime, including identifying and assessing new risks, adverse events, and side-effects specific to certain indications.
New information that is relevant to long-term safety and clinical performance of the device may emerge from PMS and PMCF activities. This new information may identify a need for PMCF studies to further assess identified issues.
· Novelty of a device
When a device displays a high degree of novelty with respect to the SOTA concerning aspects such as design, materials, substances, the principles of operation, the technology and manufacturing process, or the related clinical procedure, PMCF studies should be considered.
· Breakthrough medical devices & orphan medical devices
For guidance on PMCF for breakthrough medical devices and orphan medical devices, please refer to MDCG 2025-9 and MDCG 2024-10.
· Changes to the device
Where changes have been made to a device and where compliance with the applicable requirements has been demonstrated with respect to that change following the applicable conformity assessment procedure[footnoteRef:76], PMCF studies may be considered to further evaluate the impact of that change on the device’s safety and clinical performance.
As described in Article 5(6) of MDR
· Device associated with high level of overall risk
PMCF studies are recommended when the clinical evaluation of a device shows that there is high overall risk associated with certain indications, for example when used for certain life-threatening conditions, vulnerable patient populations, or surgically invasive procedures in high-risk anatomical locations.
· Generalising clinical data to use in routine clinical practice
When the clinical evaluation of a device provides sufficient clinical evidence for conformity assessment, but there are uncertainties regarding how representative the clinical data are to routine clinical practice, PMCF studies are recommended. For example, PMCF studies may be used for confirming a device’s long-term safety and clinical performance in a population that is broader and more representative of routine clinical practice, compared with any clinical investigations conducted in the pre-market phase. See Section 9.3.2 for examples of factors that may impact the representativeness of clinical data.
· Devices where clinical evaluation is based on clinical data from equivalent device(s)
Where a clinical evaluation is based on clinical data relating to a device for which equivalence to the device in question can be demonstrated[footnoteRef:77], the PMCF should collect sufficient clinical data, through PMCF studies where appropriate, to confirm the safety and performance throughout the expected lifetime of the device, ensure the continued acceptability of identified risks, and of detect emerging risks.
Per MDR Annex XIV, Part A, Section 3
For class III and implantable devices that are exempted from the requirement to perform pre-market clinical investigations pursuant to MDR Articles 61(4) to 61(6)[footnoteRef:78], PMCF studies (including PMCF investigations where necessary) must be performed to demonstrate the safety and performance of the device under evaluation[footnoteRef:79].
See MDCG 2023-7
Per MDR Article 61(4), second subparagraph.
· Emergence of new information relating to safety or clinical performance of equivalent or similar devices
Where new information from equivalent or similar devices is identified during PMS and PMCF[footnoteRef:80] that details aspects potentially requiring further evaluation of clinical performance or safety of the device under evaluation (e.g., new risks identified from scientific literature or other data sources), PMCF studies should be considered for the collection of clinical data relevant to these aspects, as part of the clinical evaluation of the device.
Per MDR Annex XIV, 6.2(f)
· Rare anticipated risks and undesirable side-effects
Rare anticipated risks (e.g. stent thrombosis of the coronary stent) and rare undesirable side-effects may be difficult to assess in the pre-market setting but could potentially be identified using large datasets; therefore, it may be necessary to assess the rare adverse events in PMCF studies.
Effectiveness of the mitigation for a known risk
Where known risks associated with the use of the device have been mitigated, PMCF studies may be suitable for contributing to the confirmation of the adequacy of such mitigations.
13.2 [bookmark: _Toc236912920]PMCF investigations
A PMCF investigation is a clinical investigation conducted to further assess, within the scope of its intended purpose, a device that already bears the CE marking in accordance with Article 20(1) of MDR[footnoteRef:81].
MDR Article 74(1).
The decision to conduct a PMCF investigation should take into consideration the clinical evaluation of the device, with particular consideration of any residual risks or uncertainties on long-term safety and clinical performance that may impact the benefit-risk ratio of the device.
Compared to pre-market clinical investigations, PMCF investigations are typically larger in scale with longer follow-up periods and aim to further assess safety and performance, including clinical benefit, of the medical device in a broader population of subjects and users.
13.3 [bookmark: _Toc445828594][bookmark: _Toc445907689][bookmark: _Toc445828596][bookmark: _Toc445907691][bookmark: _Toc445828598][bookmark: _Toc445907693][bookmark: _Toc445828600][bookmark: _Toc445907695][bookmark: _Toc236912921]Clinical investigations under MDR Article 74(2)
Where a clinical investigation of a CE-marked medical device is conducted outside the intended purpose of the device, this is not considered a PMCF investigation; instead, MDR Article 74(2) (and thus MDR Articles 62 to 81) applies. Such studies may play a role in collecting clinical data for the clinical evaluation of a new indication or intended purpose. Please refer to MDCG 2021-6 for further information.
[bookmark: _Toc236912922]Update the clinical evaluation and associated documentation throughout the lifecycle of the device
[bookmark: _Toc236912923]General considerations on updating the clinical evaluation
The clinical evaluation and its documentation shall be updated throughout the lifecycle of the device concerned with clinical data obtained from the implementation of the manufacturer's PMS plan and PMCF plan[footnoteRef:82].
MDR Art. 61(11)
Manufacturers are required to implement and maintain a PMS system to actively and systematically gather, record and analyse relevant data on the quality, performance and safety of a device throughout its entire lifecycle, and to draw the necessary conclusions and to determine, implement and monitor any preventive and corrective actions[footnoteRef:83].
MDR Article 83(2)
PMS regularly generates new data that need to be evaluated, as these data have the potential to change the evaluation of the benefit-risk profile and the conclusions regarding the clinical performance and clinical safety of the device.
The results of the PMS plan[footnoteRef:84] shall be summarised in:
MDR Article 83 (3)
· the PMS report for class I devices.
· the PSUR for class IIa, IIb and III devices.
The PMCF plan shall be covered by the PMS plan[footnoteRef:85] (see Section 13). The manufacturer shall analyse the findings of the PMCF and document the results in a PMCF evaluation report that shall be part of the technical documentation[footnoteRef:86]. See Section 8.1 for clinical data identifiable through PMS and PMCF activities.
Section 1.1 (b), Annex III to MDR
Section 7, part B, Annex XIV to MDR
An update of the CER is required in cases where the PMS and/or PMCF results indicate that a change is needed.
Aspects to be updated in the clinical evaluation are (not exhaustive list):
new clinical data[footnoteRef:87] available for the device under evaluation
Art. 2(48). of MDR
new clinical data available for equivalent devices (if equivalence is claimed)
new knowledge about known and potential hazards, risks[footnoteRef:88], performance, benefits[footnoteRef:89] and claims[footnoteRef:90], including
For further detail, refer to standard EN ISO 14971:2019/A11:2021 and other harmonised standards.
Art. 2(53) of MDR
Claims made by the manufacturer on the clinical performance and clinical safety of the device under evaluation.
· data on clinical hazards seen in other products (e.g. hazard due to substances and technologies)
· changes concerning the SOTA, such as changes to applicable standards and guidance documents, new information relating to the medical condition managed with the device and its natural course, medical alternatives available to the target population
other aspects identified during PMS.
When updating the clinical evaluation, the evaluators should verify:
if the benefit-risk profile, undesirable side-effects (whether previously known or newly emerged) and risk mitigation measures are still:
· compatible with a high level of protection of health and safety and acceptable taking into account the generally acknowledged SOTA
· correctly addressed in the information materials supplied by the manufacturer of the device
· correctly addressed by the manufacturer's current PMS and PMCF plans
if existing claims are still justified
if any new claims or conclusions the manufacturer intends to make are justified.
When updating the clinical evaluation, if the manufacturer concludes there is not sufficient clinical evidence to be able to confirm conformity with the GSPRs, the manufacturer will need to take necessary corrective and preventive actions[footnoteRef:91], which may include no longer placing the device on the market until conformity is restored.
Article 83(4) of MDR,
While clinical evaluation requires data from PMS and PMCF, activities, it also generates new information that may lead change in:
· the PMS and PMCF plan
· the risk management process resulting in changes to the manufacturer’s risk management documents
· the information material to be supplied with the device.
Moreover, MDR foresees that the SSCP[footnoteRef:92], which is required for class III and implantable devices, shall include the summary of clinical evaluation and relevant information on PMCF[footnoteRef:93]. Therefore, the SSCP, if indicated, should be updated and aligned with the clinical evaluation, if needed.
See MDCG 2019-9
Article 32(2) of MDR
[bookmark: _Toc236912924]Frequency of updates
The manufacturer should define and justify the frequency at which the clinical evaluation and related documentation need to be actively updated.
Specific MDR requirements for frequency apply for:
· the PMCF evaluation report, that shall be updated at least annually for class III and implantable devices[footnoteRef:94];
Art. 61(11) of MDR
· the PSUR, that shall be updated at least annually for class IIb and class III devices and at least every two years for class IIa devices[footnoteRef:95].
Art. 86 of MDR
The need for an update of the clinical evaluation and its documentation and of the SSCP should be considered, for class III and implantable devices, as a consequence of the findings of the PMCF evaluation report and PSUR annual update[footnoteRef:96].
Art. 61(11) of MDR requires to update at least annually the PMCF evaluation report and the PSUR for class III and implantable devices. The CER should be updated consistently as per Annex XIV part B, section 7
For other risk classes, irrespective of the frequency of update defined by the manufacturer, the clinical evaluation needs to be actively updated when the manufacturer receives new information from PMS and PMCF that has the potential to change the current evaluation.
When defining and justifying the clinical evaluation documentation frequency of updates, the manufacturer should typically consider:
· whether the device carries significant risks
(e.g. based on design, materials, components, invasiveness, clinical procedures, high-risk anatomical locations, high-risk target and vulnerable populations (e.g. paediatrics, elderly), severity of disease/ treatment challenges).
· the likelihood of the new information becoming available on the device, taking into consideration:
· novelty
· relevant changes in clinical sciences, materials sciences or other sciences related to the device under evaluation
· the current level of confidence in the evaluation of clinical performance and clinical safety of the device; in particular, the manufacturer should consider
· the available clinical data
· the total number of devices used so far in the market and expected reporting rates under the vigilance system
· whether there are risks and uncertainties or unanswered questions, in the medium or long-term, that would influence the frequency of updates
· [bookmark: _Hlk169791372]whether design changes or changes to manufacturing procedures have been made (if any) which could impact the safety and/or performance of the device.
Table 2. summarizes the update frequencies for clinical evaluation and related processes documentation.
[bookmark: _Ref172624032]Table 2. Clinical evaluation and related processes documentation frequency of update
Document
Required for
Frequency of update
Clinical evaluation documentation (CEP, CER and related documents listed section 12.1)
All devices
· Class III and implantable: the necessity to update to be considered annually based on PMCF evaluation report and PSUR annual update.
· other device classes: when necessary, depending on
· - clinical data obtained from the implementation of the manufacturer's PMCF plan and PMS plan
· - other aspects mentioned in the section.
PMCF plan
All devices (unless a justification as to why a PMCF is not applicable is provided (see Section 13)
When necessary, depending on clinical data obtained from the implementation of the previous manufacturer's PMCF plan and the PMS plan
PMCF evaluation report
All devices (unless a justification as to why a PMCF is not applicable is provided (see Section 13)
· Class III and implantable devices: annually
· Other devices: as determined by the manufacturer in the PMCF plan
PSUR
Class IIa, IIb and III
· Class IIb and III: at least annually
· Class IIa: at least every 2 years
PMS report
Class I
When necessary
SSCP
Class III and implantable devices
The necessity to update to be considered annually based on PMCF evaluation report and PSUR annual update.
[bookmark: _Toc446499050][bookmark: _Hlk145430929]
[bookmark: _Toc236912925][bookmark: _Hlk167800612]The role of the notified body in the assessment of clinical evaluation reports
The notified body plays a key role in the assessment and verification of clinical evaluation reports and supporting documentation provided by manufacturers to support demonstration of conformity of a device with the GSPRs of MDR.
MDCG documents which include best practice guides, checklists and forms in relation to the activities of Notified Bodies, such MDCG 2020-13[footnoteRef:97], should be consulted.
MDCG 2020-13: Clinical evaluation assessment report template
When assessing the clinical evaluation as part of the conformity assessment procedure, the notified body shall consider the requirements in Section 4.5.5 of Annex VII to MDR.
Where demonstration of conformity with the relevant GSPR(s) based on clinical data is not deemed appropriate, this must be adequately justified by the manufacturer (see Section 7.2.6). The notified body must review the manufacturer’s justification, the adequacy of data presented and whether or not conformity is demonstrated. Nevertheless, a clinical evaluation is still required and the above information and an evidenced justification should be presented in the CER for the device in question (see Section 7.2.6).
[bookmark: _Toc236912926]Art 54 (1) devices: Clinical evaluation consultation procedure
Article 54 of MDR outlines a mandatory clinical evaluation consultation procedure (CECP) for certain medical devices.
[image: ]
Figure 2: Schematic overview of the Clinical Evaluation Consultation Procedure
As a first step, the notified body needs to consider whether the device under evaluation falls into the risk classes and types[footnoteRef:98] that qualify for consultation by expert panels in regard to aspects of clinical evaluation assessment, i.e., class III implantable medical devices and class IIb active devices intended to administer and/or remove a medicinal product (“ARMP”).
Article 54(1) of MDR
If the qualification criteria are fulfilled, the notified body then needs to consider the three exemption criteria described in Article 54(2) of MDR. The CECP is not required if any of these 3 criteria are fulfilled. The document MDCG 2019-3 rev.1 “Clinical evaluation consultation procedure exemptions Interpretation of article 54(2)b” provides guidance on the exemption criteria listed under Article 54 paragraph (2)(b).
Having considered the qualification criteria and the exemption criteria, the notified body needs to notify the competent authorities, the authority responsible for notified bodies and the Commission whether or not the CECP is to be applied (Article 54(3)).
Should a device qualifies for and requires a CECP, the notified body must follow the procedure outlined in MDR Annex IX Section 5.1 (also referenced in Section 6, Annex X to MDR) and transmit the CECP dossier to the Secretariat of the expert panels in the field of medical devices designated by the Commission Implementing Decision (EU) 2019/1396. The dossier will include the documents outlined in point 5.1(a) of Annex IX to MDR, along with the administrative documents requested by the Secretariat.
As part of this dossier, the notified body will submit a final CEAR, i.e. only necessary changes as outlined below that do not modify the clinical evaluation assessment are possible after this submission. All applicable sections of this should be completed, relevant conclusions reached and corresponding boxes ticked for the report to be complete. MDR Annex VII point 4.6 mandates that the CEAR clearly documents the conclusions of the assessment of the manufacturer’s clinical evaluation. Furthermore, the CEAR will be based on a standard format containing a minimum set of elements determined by the MDCG. MDCG 2020-13 “Clinical evaluation assessment report template” represents the minimum content for a CEAR. The CEAR will also make a recommendation to support a final review, and a final decision to be taken by the notified body.
Expert panels who are conducting a clinical evaluation consultation procedure will assess the CEAR, however they do not have access to the complete conformity assessment for the device and associated procedures and documentation. To enable the expert panel work, the CEAR must provide sufficient information with respect to the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the indications, and the PMCF plan.
Notified bodies will be informed about the result of the panel consultations via upload of:
· the decision report of the screening experts in cases where no opinion is needed;
· the opinion report of the respective thematic panel or sub-group at the end of the process in cases where an opinion is needed.
If an opinion is received within the 60-days timeline, the notified body is obliged to give due consideration to the expert panel scientific opinion. The notified body will, where applicable and as appropriate, take the measures outlined in MDR Annex IX point 5.1(g).
[bookmark: _Toc161933207][bookmark: _Toc446499051]In order to take into account the opinion of the expert panel, or in order to reflect changes covering the elements described in indent (g) of point 5.1 of Annex IX to MDR the notified body may only modify “Section I” of the CEAR after receiving the result of the consultation. At this stage, the notified body may not further modify the CEAR based on supplemental clinical data and evidence submitted by the manufacturer after the delivery of an opinion. However, the notified body may decide not to follow the advice or to follow only part of it. In this case, it will need to provide a full justification outlining the reasons which will be published together with the opinion
[bookmark: _Toc236912927]Appendices
[bookmark: _Ref164071682][bookmark: _Ref164530083][bookmark: _Ref164534091][bookmark: _Ref164861953][bookmark: _Ref165982333][bookmark: _Ref166597808][bookmark: _Ref166607233][bookmark: _Ref170832415][bookmark: _Ref172553404][bookmark: _Ref172554081][bookmark: _Ref172555065][bookmark: _Ref172558574][bookmark: _Ref172637416][bookmark: _Ref172637667][bookmark: _Ref172731640][bookmark: _Ref172731801][bookmark: _Ref233282644][bookmark: _Toc236912928][bookmark: _Ref433633423][bookmark: _Toc446499052][bookmark: _Ref433633264][bookmark: _Ref433190420]State of the art for the clinical evaluation
A literature review that identifies and describes SOTA[footnoteRef:99] in medicine should be prepared for the clinical evaluation. The focus of this review should be on:
As defined in section 4
(i) the clinical condition(s) and/or medical purpose(s) for which the device under evaluation is intended to be used (the clinical background), and
(ii) (ii) the current technical capabilities or medical options that are relevant in this context.
The SOTA description should include a comprehensive overview of relevant medical options that address the same intended purpose as the device under evaluation in current clinical practice. This includes (non-exhaustive list) conservative management, non-surgical options (e.g., physical therapy, physiotherapy, pharmaceuticals), and interventional options (e.g., interventional radiology etc.), as well as the absence of any available medical option. In addition, combinations of several therapies, treatments, diagnostic devices, procedures and technologies may be relevant. A specification of parameters that are used in the current clinical practice to evaluate, qualitatively and quantitatively, the safety and performance of the available medical options should be included in the SOTA description. These parameters shall be used in the clinical evaluation to determine the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device under evaluation[footnoteRef:100].
Indent six, section 1a, part A, Annex XIV to MDR
There is no single database or registry that defines what is considered SOTA in medicine. It is important to acknowledge that although in some scenarios there may be “a gold standard” that is well agreed among the international clinical community, SOTA in most cases would consist of multiple alternative options. In addition, what is considered SOTA may be subject to regional or contextual differences, which needs to be considered.
Establishing and describing SOTA is central to the clinical evaluation, and it is used as a reference throughout the clinical evaluation. Clinical evaluators (and in general, manufacturers, developers) must have a strong understanding of the SOTA relating to the device under evaluation.
Note that results from SOTA literature review does not meet the definition of clinical data.
[bookmark: _Toc158730989][bookmark: _Toc236912929][bookmark: _Toc153173208]A1.1 When to identify State of the Art
Clinical evaluation is typically initiated during device development. Considering the importance of SOTA in the development process, the work to identify and describe it should also be initiated early during product development. SOTA is, however, dynamic, and may change with development of new technologies but also as new information emerges regarding the natural course of the medical condition (if any) that is managed/diagnosed. SOTA revision should be considered when updating the clinical evaluation (see section 14) to ensure that any relevant changes are reflected in the documentation.
[bookmark: _Toc236912930]A1.2 Identification of data and information (literature searches)
Relevant data and information for the SOTA description could come from several different sources, such as academic databases, government and organisations websites and include (list not exhaustive) systematic reviews, meta-analyses, clinical practice guidelines, consensus statements and recommendations speciality medical societies, international standards, and Health technology assessment (HTA) reports. Literature searches are likely to need a broad scope, and several different searches would typically need to be conducted. Screening citations in other documents, such as guidelines, represents another important approach to identifying relevant data.
In a similar manner to the documentation of the literature search for clinical data (see section 8), a specific SOTA literature search protocol that specifies the scope, objective and methods for identification, selection, and collection of the relevant information should be compiled. The timeframe selected in the literature search protocol should be clearly justified. Search results should be documented in a SOTA literature search report, including sources used, search questions, search terms, and applied selection criteria, quality control measures, results, number and type of literature found to be relevant. For more information about search procedures, see section Appendix A6, which, although focusing on clinical data, contains some generally applicable considerations.
[bookmark: _Toc236912931]A1.3 Documenting
The work to identify SOTA should be documented separately from the literature review on the clinical data of the device under evaluation or equivalent device. The SOTA literature search protocol and report, and the SOTA description should be documented in dedicated documents or sections of the CEP or of the CER. If in separate documents, they should be clearly referenced in the CEP and CER.
The content of the SOTA description should cover the following:
· brief summary of the literature search strategy and search results
· description, natural course and consequences of the medical conditions concerned including the different clinical forms, stages and severities of the conditions if appropriate. If applicable, frequency (incidence/prevalence) in the general population, by age group, gender, ethnicity, familiar predispositions and genetic aspects should be considered. The relation of these aspects to the intended purpose of the device under evaluation should also be described
· historical context and developments in the field, if relevant
· applicable common specifications, standards and guidance documents, including medical society guidelines, that are relevant for the clinical evaluation
· description of identified alternative medical options (e.g., available therapeutic, management, diagnostic options):
· summary of advantages and disadvantages of the different medical options
· description of the expected benefits and risks (nature, extent, probability, duration, frequency)
· description of undesirable side-effects and other risks (including the nature, severity, probability and duration of acceptable harm)
· potential hazards (e.g., resulting from technologies, substances, manufacturing procedures, and impurity profiles) and approaches to minimize such risks
· benefit-risk profiles and limitations of these options in relation to the different clinical forms, stages, and severities of the medical conditions and in relation to different target populations
· diverging opinions of healthcare professionals as to the use of the different medical options, if applicable
· types of users.
· an indicative list of parameters that will be used to determine the acceptability of the benefit-risk ratio for the device under evaluation. This list should be based on the information collected through the SOTA literature review.
[bookmark: _Toc446499054][bookmark: _Ref164257912][bookmark: _Ref164529750][bookmark: _Ref164533901][bookmark: _Ref166607076][bookmark: _Ref233288598][bookmark: _Toc236912932]Device description - typical contents
[bookmark: _Hlk225180448]The description of the device under evaluation should be detailed enough to allow for a valid evaluation of the state of compliance with GSPRs, the retrieval of meaningful literature data and, if applicable, the assessment of equivalence. A non-exhaustive list of typical content to consider, if applicable, is:
· name, trade name and, if available, alternative brand name, the Basic UDI-DI where applicable, models/ various configurations/variants, version, sizes, parts/components of the device, including software and accessories
· device risk class and applied classification rules
· generic device group to which the device belongs (e.g. biological artificial aortic valve)
· whether the device is being developed/ undergoing initial CE-marking/ is CE-marked
· whether the device is currently on the market in the Union or outside the Union, and for how long; justification if it is considered that the device belongs to a well-established technology and device history: description of all clinically relevant changes, with rationale for the change
· intended purpose of the device, including:
· exact indication (if applicable)/ identification of medical fields concerned/ name of disease or relevant medical condition/ clinical form, stage, severity/ symptoms or specific medical purposes (e.g. aspects to be treated, managed or diagnosed)
· target group/ patient populations (e.g. adults/ children / infants/ elderly or specific age group, pregnant/ breastfeeding women or, other aspects)
· intended user (for professional user / lay user)
· organs / parts of the body / tissues or body fluids contacted by the device
· duration of use or contact with the body
· device lifetime
· repeated applications, including any restrictions as to the number or duration of re-applications
· contact with mucous membranes/ invasiveness/ implantation
· contraindications
· precautions required by the manufacturer
· single use / reusable.
· general description of the medical device including:
· key functional elements, e.g. its parts/components (including a concise physical and chemical description, software, if appropriate), its formulation, its composition, its functionality and, where relevant, its qualitative and quantitative composition
· the technical specifications, mechanical characteristics
· sterility
· radioactivity
· how the device achieves its intended purpose/ treatment and management options
· principles of operation/ mechanism of action scientifically demonstrated
· materials used in the device with focus on materials coming in contact (directly or indirectly) with the patient/ user, description of body parts concerned
· whether the device incorporates a medicinal substance (already on the market or new), animal tissues, blood components, the purpose of the component
· whether the device incorporates electronic programmable systems, including software, or software that are devices in themselves
· whether the device incorporates or consisting of nanomaterial
· whether the device is composed of substances or combinations of substances
· medical alternatives to the device with reference to the SOTA description
· description of the degree of novelty and the innovative aspects of the device
· whether the device is intended to cover unmet medical needs with consideration to its orphan or breakthrough device status, if relevant
· if the device is equivalent to an existing device for which following information should be given[footnoteRef:101]:
See MDCG 2020-5 and to Appendix II of MDCG 2023-7 for guidance on equivalence. For further guidance on demonstration of equivalence of Annex XVI products, please refer to MDCG 2023-6.
· name or trade name(s), models, sizes, settings components, including software and accessories
· intended performance, including the technical performance of the device intended by the manufacturer, the intended clinical benefits, claims regarding clinical performance and clinical safety that the manufacturer intends to use
· for devices based on predecessor devices: Name, models, sizes of the predecessor device, whether the predecessor device is still on the market, description of the modifications, date of the modifications.
[bookmark: _Ref164529753][bookmark: _Ref165303152][bookmark: _Ref167309998][bookmark: _Toc236912933][bookmark: _Hlk164627990]Clinical evaluation plan typical content
Depending on the stage in the lifecycle of the product, the following aspects should be considered for inclusion in the CEP. Mandatory aspects foreseen by MDR are indicated with “*”.
[bookmark: _Hlk165376151]Aspects (not an exhaustive list)
· Identification and description of the device covering all sizes, variants, models, accessories and configurations. For additional information, see Appendix A2.
· a specification of the intended purpose of the device (see Appendix A2 for more information on the intended purpose content) *.
· a clear specification of intended target groups with clear indications and contra-indications, where applicable*
· Description of whether:
· the clinical evaluation is based on clinical data of the device under evaluation and/or an equivalent device
or
· if demonstration of conformity with GSPRs based on clinical data is not deemed appropriate.
· Description of the SOTA, including the planned steps to identify it (see Appendix A1). Note that the SOTA analysis may also be documented in the CER or in a dedicated document. The SOTA literature search protocol and report may also be in separate documents
· If equivalence will be claimed, demonstration of equivalence is documented in the CEP, in the CER or in a dedicated document (see MDCG 2020-5 for more information on equivalence).
· a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters*.
· an identification of the GSPRs that require support from relevant clinical data*. See appendix A9 for more information.
· whether there are any design features of the device, or any indications or target populations, that require specific attention. The clinical evaluation should cover any design features that pose specific performance or safety concerns (e.g. presence of medicinal, human or animal components), the intended purpose and application of the device (e.g. target treatment group and disease, proposed warnings, contraindications, precautions, and method of application) and the specific claims made by the manufacturer about the clinical performance and clinical safety of the device.
· For CE marked devices, whether the manufacturer has introduced/ intends to introduce any relevant[footnoteRef:102] changes, including
Many changes are not clinically relevant (such as administrative changes to the labelling) and need not be considered for setting up a Clinical Evaluation plan.
· design changes,
· changes to materials and manufacturing procedures,
· changes to the information materials supplied by the manufacturer (label, IFU, available promotional materials including accompanying documents possibly foreseen by the manufacturer) or other claims,
· and whether the claim of equivalence to an existing device is still appropriate.
· For CE marked devices, whether there are any specific clinical concerns that have newly emerged and need to be addressed.
· Planning of clinical evaluation stages 1-3:
· Methods for clinical data identification, specifying the data source(s) and type(s) to be used in the clinical evaluation. Data relevant to the clinical evaluation may be generated and held by the manufacturer or available from scientific literature. The literature search protocol, as referred to Appendix A6, may be included in the CEP or may be in a separate document. For additional information, see Section 8 (Identification of available clinical data), and Appendix A5 (Sources of literature) and Appendix A6 (Data not held by the manufacturer search, key elements).
· Methods for the appraisal of relevant clinical data (see Section 9). The appraisal plan may be included in the CEP or in a separate document.
· Methods for the analysis of relevant clinical data (see Section 10), including:
· a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects*.
· an indicative list and specification of parameters to be used to determine, based on the SOTA in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device*.
· an indication of how benefit-risk issues relating to specific components such as use of pharmaceutical products, non- viable animal tissues or human tissues, are to be addressed*.
· The analysis plan may be included in the CEP or may be in a separate document.
· the CDP should outline the progression of clinical investigations, starting from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations*. Milestones and potential acceptance criteria should be described.
[bookmark: _Ref233282631][bookmark: _Toc236912934][bookmark: _Hlk158044726]Clinical data for medical device software
To generate clinical data for the clinical evaluation of MDSW, the manufacturer may consider performing studies to assess the device’s safety or performance. If the study in question prospectively enrols patients as subjects and prospectively collects their data for the purpose of assessing the safety or performance of the MDSW, this study should qualify as a clinical investigation (per MDR Article 2(45)).
As acknowledged in MDCG 2021-6, if the patient data to be used has not been prospectively collected from enrolled subjects for the purpose of the study (e.g., extracted from pre-existing health records), this study would generally not qualify as a clinical investigation.
However, studies using previously collected patient data can produce valid clinical data for the purpose of clinical evaluation of MDSW, provided each of the following is true:
• the information that is produced from the study concerns the device’s safety or performance and is generated from the use of the device[footnoteRef:103]. Uniquely in the case of MDSW, the “use of the device” may also refer to using the device on a previously collected dataset; and
First line of Article 2(48) of MDR
• the study is reported in peer reviewed scientific literature as clinical experience of the device under evaluation[footnoteRef:104].
Third indent of Article 2(48) of MDR
As with all clinical data, such data would need to be evaluated in line with MDR and additional clinical data may be needed to provide sufficient clinical evidence per MDR Article 61(1)[footnoteRef:105]. It should also be noted that, while these data may qualify as clinical data, they would not qualify as clinical investigations. Therefore, the requirement for non-CE marked class III MDSW to conduct a clinical investigation per MDR 61(4) cannot be met using these studies.
For further information see MDCG 2020-1 “Guidance on Clinical Evaluation (MDR)/Performance Evaluation (IVDR) of Medical Device Software
Please note, the above studies are distinct from studies/activities conducted solely to collect patient data that is subsequently used to train MDSW (e.g., via machine-learning). Patient data collected from these studies/activities would not be considered clinical data but may be useful for training the MDSW and generating relevant data the purpose of pre-clinical evaluation.
[bookmark: _Ref164071656][bookmark: _Ref164160700][bookmark: _Ref165982677][bookmark: _Ref165986496][bookmark: _Ref165986648][bookmark: _Ref167310513][bookmark: _Ref233288458][bookmark: _Toc236912935][bookmark: _Toc446499055]Sources of clinical data not held by the manufacturer (literature)
[bookmark: _Hlk141803661]There are several different sources that can be searched for clinical data relevant for the clinical evaluation. A comprehensive search strategy is required that should be documented and justified.
Scientific databases
Scientific databases are important sources of clinical data. It should be noted that information coverage and search features available in scientific databases may not be guaranteed and can change with time, and searches for clinical data should typically involve multiple databases. Criteria for selecting adequate databases need to be defined and re-evaluated on a regular basis. The manufacturer should justify which databases are to be used for the clinical evaluation.
Below is a (non-exhaustive) suggested list of examples of databases (it is not expected that manufacturers will use all of these).
· PubMed is a free resource containing citations and abstracts of biomedical literature. It does not include full text journal articles. Citations in PubMed primarily stem from the biomedicine and health fields, and related disciplines such as life sciences, behavioural sciences, chemical sciences, and bioengineering.
· Embase (Excerpta Medica database) is Elsevier’s biomedical database that focuses on drug and pharmaceutical research, medical devices, and clinical medicine.
· Scopus is Elsevier´s multidisciplinary abstract and citation database.
· CINAHL is an index of the nursing and allied health literature. It indexes publications from several of the prominent nursing associations and from many publishers.
In addition to these databases, there are databases that provide systematic reviews of scientific literature. Two important databases are:
· The Cochrane Library: this is a collection of databases in medicine and other healthcare specialties.
· PROSPERO (international prospective register of systematic reviews) is an international database of prospectively registered systematic reviews in health and social care, welfare, public health, education, crime, justice, and international development, where there is a health-related outcome. PROSPERO is produced by CRD and funded by the National Institute for Health Research (NIHR).
Other sources of clinical data
Other sources can provide additional clinical data to that listed above (see examples below), many of which are available as open access. Several universities provide information about different resources as well as links to them. Moreover, information about sources, searches and use of data is provided as a part of Cochrane training[footnoteRef:106].
https://training.cochrane.org/
Examples of other sources, together with information regarding type of clinical data and information that can be found, are listed below:
· Manufacturers´ websites, EUDAMED[footnoteRef:107], websites of European competent authorities and other sites, publish field safety corrective actions and (partial) vigilance reports that can be relevant for the device under evaluation.
The module in EUDAMED for safety reporting is not functional at the time of release of this document.
· Besides the sources of FSCAs mentioned above, non-EU databases managed by other agencies such as the Therapeutic Goods Administration, Australia (TGA), Medicines and Healthcare products regulatory agency in the UK (MHRA), the Food and Drug Administration, US (FDA), contain medical device reports submitted under mandatory reporting schemes (by e.g. manufacturers, importers, and device user facilities) and voluntary reporters such as health care professionals, patients, and consumers.
· Medical device registries/registers and disease registries, especially those that are governed by national bodies or speciality medical associations, can be useful sources for RWD. RWD may be used in for example retrospective studies and registries themselves also issue annual reports (the level of detail may however be low).
· Clinical investigations conducted under MDR will be reported in a specific module in EUDAMED [footnoteRef:108]
The module is not functional at the time of release of this document.
· The ClinicalTrials.gov (US government website) and WHO International Clinical Trials Registry Platform (ICTRP) can be used to identify clinical studies. It should be noted that although these databases should include information about study results, once studies have been completed, results are not always reported (in a timely manner).
[bookmark: _Toc446499056][bookmark: _Ref164160714][bookmark: _Ref165982726][bookmark: _Ref165982736][bookmark: _Ref165990602][bookmark: _Ref167459476][bookmark: _Ref233808297][bookmark: _Ref233808485][bookmark: _Toc236912936]Identification of available clinical data not held by the manufacturer, key elements for literature searches
Identification of available clinical data not held by the manufacturer is conducted through literature searches that are based on a literature search protocol and reported in a literature search report. The literature search protocol(s) (there may be several) may be part of the CEP and the literature search report of the CER, or they may be standalone documents that are referenced in the other clinical evaluation documents.
[bookmark: _Toc236912937]A6.1 Methods
The selection of clinical data should be objective and justified and include all relevant publications, reports, assessments, etc., presenting both favourable and unfavourable data. It is important that the clinical evaluators can assess the degree to which the selected data reflect the intended use of the device.
The search strategy should be based on carefully constructed research questions. These should be consistent with the scope of the clinical evaluation and carefully constructed using objective, non-biased, systematic search methods. Examples include (non-exhaustive list):
· PICO (patient characteristics, type of intervention[footnoteRef:109], control, and outcome queries)
The term intervention includes therapies, diagnostic measures, measures for the management of diseases or medical conditions.
· Strategies described in the Cochrane Handbook for Systematic Reviews of Interventions
· PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement
· MOOSE Proposal (Meta-analysis Of Observational Studies in Epidemiology)
Important inputs for the research question(s) are the device description and the intended purpose and performance of the device including any claims on clinical performance and clinical safety which the manufacturer will make. Also, information such as device or procedure specific risks identified within the risk management process may provide important input.
Searches should aim to be as extensive as possible to ensure that as much of the relevant data as possible are retrieved. It is, however, necessary to strike a balance between striving for comprehensiveness and maintaining relevance when developing a search strategy.
Developing a search strategy is an iterative process in which the terms that are used may need to be modified, based on what has already been retrieved. It is often difficult to decide in a scientific or objective way when a search is complete, and the search can stop. It may be appropriate to stop searches if adding a series of new terms to a database search strategy yields no new relevant records or when removal of terms or concepts results in missing relevant records. Another consideration is the amount of evidence that has already accrued: in topics where evidence is scarce, authors might need to be more cautious about deciding when to stop searching[footnoteRef:110].
More guidance can be found in the Cochrane training handbook and the references therein such as Booth A. How much searching is enough? Comprehensive versus optimal retrieval for technology assessments. Int J Technol Assess Health Care. 2010 Oct;26(4):431-5. doi: 10.1017/S0266462310000966. Epub 2010 Oct 6. PMID: 20923586.
At a basic level, investigation is needed as to whether a strategy is performing adequately. One simple test is to check whether the search is finding already known publications or publications that have been included in other similar reviews. It is not enough, however, for the strategy to find only those records, as this may demonstrate that the strategy is biased towards known studies and other relevant records might be missed. In addition, citation searches and reference checking are useful to verify the strategy performance and may be a source of information in their own right.
It is important to document any information found in a structured way to allow retrieval when needed. For example, information about ongoing and/or unpublished trials needs to be carefully documented, as this information may not be accessible at a later time.
It should be noted that a single study may have more than one publication related to it (or record for it), and each of these publications or other records may contribute useful information. Note, however, the risk of duplication of the same data in different publications. Individual studies may also be duplicated in systematic reviews published in the peer reviewed literature. Depending on the nature and quality of such reviews, it may be appropriate to either remove the individual publication from the clinical evaluation, or the systematic review containing the data of the individual publication, to avoid duplication. Any such removal should be documented and justified.”
Also referenced in the Cochrane training handbook are publications with further guidance on some aspects specific for searches for medical devices[footnoteRef:111], and a checklist (PRESS 2015 Guideline Evidence-Based Checklist) that may be useful[footnoteRef:112].
Cooper C, Dawson S, Lefebvre C. Searching for medical devices - Practical guidance. Res Synth Methods. 2022 Jan;13(1):144-154. doi: 10.1002/jrsm.1524. Epub 2021 Nov 16. PMID: 34494371.
McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol. 2016 Jul;75:40-6. doi: 10.1016/j.jclinepi.2016.01.021. Epub 2016 Mar 19. PMID: 27005575.
[bookmark: _Toc236912938]A6.2 Search protocol and report
The purpose of a search protocol is to plan the search for data before executing the search. The purpose of a search report is to present the results from the search(es), including any deviations from the plan.
The table below shows typical content of the literature search plan (LSP) and the literature search report (LSR).
Topic
LSP
LSR
General information
Name, trade name and, if available, alternative brand names, UDI-DI where applicable, models, version of the device
X
X
Scope and purpose of the literature search (should be consistent with scope of clinical evaluation and the review questions)
X
X
Search Input:
-
-
Sources of data with justification for choice
X
Detailed description of the search strategy including:
· which scientific literature databases, with justification;
· other electronic and non-electronic sources of published and non-published information, with justification;
· attempts to identify all relevant published literature;
· strategies for addressing the potential for duplication of data across multiple publications;
· supplemental strategies used to enhance the sensitivity of search(es), e.g., checking bibliography of articles retrieved and hand searching of literature
X
Search terms and any limits (e.g., type of clinical study, languages)
X
Period covered by search (i.e., start and end dates of search(es))
X
Selection criteria (exclusion/inclusion criteria) to be applied with justification for their choice
X
Search Output:
-
-
Reference to the search protocol(s)
X
Date of search, person(s) responsible for executing the search(es), databases used[footnoteRef:113]
As it is likely to be several searches, this applies to each search conducted.
X
Period covered by search
X
Sources used to identify data
X
Exact search strings used (including Boolean operators: AND, OR, and NOT) and any limits applied
X
Description of any deviations from the Literature search plan with justifications
X
Selection criteria applied
X
Results from the literature search (including the selection process, preferably illustrated using e.g., PRISMA flow diagram(s)[footnoteRef:114] or equivalent summary)
Available with conditions here PRISMA 2020 flow diagram — PRISMA statement
X
Method used to identify and remove duplicates
X
If applied, supplemental strategies used to enhance the sensitivity of search
X
Complete list of retrieved publications, preferably organized by performance and safety
X
Complete list of excluded publications with reasons for exclusion[footnoteRef:115]
Non-relevant publications may be excluded based on abstracts if they are not related to the clinical evaluation do not e.g., contain information relating to the device under evaluation (or equivalent device).
X
Additional documents:
-
-
Full text copies of relevant documents
Z[footnoteRef:116]
Will be a part of the technical documentation for the clinical evaluation.
Full-text copies of relevant publications, data, and other information should be annexes to the CER and should be available for those conducting the clinical evaluation and the conformity assessment.
The use of images to present the selection process in the literature search and tables to present more detailed results of searches in the CER (See Section 12 and Appendix A11) is encouraged.
[bookmark: _Toc446499060][bookmark: _Ref164159823][bookmark: _Ref164529587][bookmark: _Ref165365283][bookmark: _Ref233282403][bookmark: _Ref233282452][bookmark: _Ref233288641][bookmark: _Ref233808253][bookmark: _Toc236912939]Appraisal of relevant clinical data - examples of studies that lack scientific validity for demonstration of clinical performance and/or clinical safety
a. Lack of information on elementary aspects:
For example, reports and publications that omit disclosure of one or more of the following (non-exhaustive)[footnoteRef:117]:
Reporting guidelines for different study types can be found at https://www.equator-network.org
· the methods used
· the identity of products used
· numbers of patients exposed
· what the clinical outcomes were
· all the results the clinical study or investigation planned to investigate
· undesirable side-effects that have been observed
· confidence intervals/calculation of statistical significance/other relevant statistical methods
· specification of whether intention-to-treat and/or per protocol analysis was conducted, including definitions and results of the analysis.
b. Numbers too small for statistical significance – inadequate statistical power
Includes publications and reports with inconclusive preliminary data, inconclusive data from feasibility studies, anecdotal experience, hypothesis papers and unsubstantiated opinions.
c. Improper statistical methods
This includes:
· results obtained after multiple subgroup testing, when no corrections to confidence intervals/p-values have been applied for multiple comparisons
· calculations and tests based on a certain type of distribution of data (e.g., Gaussian (parametric) distribution with its calculations of mean values, standard deviations, confidence intervals, t-tests, other tests), while the type of distribution is not tested, the observed data distribution is not consistent with the assumed set of parameters, or the data have not been transformed.
d. Lack of adequate controls
In the following situations, bias or confounding are probable in single arm-studies, non-blinded studies, and in studies that do not include appropriate controls:
· when results are based on subjective endpoint assessments (e.g., pain assessment)
· when the endpoints or symptoms assessed are subject to natural fluctuations (e.g. regression to the mean when observing patients with chronic diseases and fluctuating symptoms, when natural improvement occurs, when the natural course of the disease in a patient is not clearly predictable)
· when effectiveness studies are conducted with subjects that are likely to take or are foreseen to receive effective co-interventions (including over-the-counter medication and other therapies)
· when there may be other influencing factors (e.g. outcomes that are affected by variability of the patient population, of the disease, of user skills, of infrastructure available for planning/ intervention/ aftercare, use of prophylactic medication, other factors)
· when there are significant differences between the results of existing publications, pointing to variable and ill controlled influencing factors.
In the situations described above, it is generally not adequate to draw conclusions based on direct comparisons with external or historic data (such as drawing conclusions by comparing data from a clinical investigation with device registry data or with data from published literature).
There are study designs that may adequately eliminate or control for bias and confounders through their design and conduct, which may in turn allow direct comparisons and conclusions to be drawn, such as randomised controlled design, cross-over design, or split-body design.
e. Loss to follow-up
This includes:
· studies that experience high degree of participant attrition and loss to follow up
· Inadequate capture of the flow of participants from recruitment, screening, study inclusion, randomisation and allocation of intervention (if applicable), outcome assessment, follow-up, and analysis.
Details on loss to follow-up, including numbers of subjects lost to follow-up in each study arm, reasons why subjects leave the study, and the results of sensitivity analysis, should be fully disclosed in reports and publications.
f. Misinterpretation by the authors
Includes conclusions that are not in line with the results section of the report or publication, such as:
· reports and publications not correctly addressing lack of statistical significance/confidence intervals that encompass the null hypothesis
· effects too small for clinical relevance.
g. Illegal activities
Includes clinical investigations not conducted in compliance with local regulations. Clinical investigations are generally expected to be designed, conducted and reported in accordance with GCP standards, such as ISO 14155:2020 or a comparable standard, and in compliance with local regulations and the Declaration of Helsinki. Clinical investigations conducted in the EU (which commenced after application of MDR (EU Regulation 2017/745) on 26 May 2021) must comply with the relevant requirements in Chapter VI and Annex XV of MDR, and with applicable national provisions. Clinical investigations conducted in the EU which commenced before application of MDR must comply with Directive 93/42/CE and 90/135/CEE. For clinical investigations performed in countries outside of the EU, they must comply with the applicable legal requirements in those countries.
[bookmark: _Ref164529601][bookmark: _Toc236912940]Use of data from retrospective studies
A retrospective study is one in which participants’ baseline information, use of a medical device and the outcomes of interest to the study are obtained from information that existed prior to the commencement of the study.
Data obtained from retrospective studies has the potential to yield useful information to aid in the clinical evaluation of a medical device. For example, retrospective studies can be useful to establish an assumption of associations between an input and outcomes or contribute to the overall body of evidence. Retrospective studies may be useful for the purpose of investigating the epidemiology and/or natural history of a condition for which a device is indicated. Retrospective studies can also be useful in generating hypotheses which may be further investigated in clinical investigations. Retrospective studies can have a more defined role in the post-market setting, for example, to monitor the safety and assess the "real world" impact of a medical device. This information might be useful in providing confirmatory data regarding the safety and performance of the device.
However, the use of this data can pose specific challenges. The data was not collected in a predesigned proforma as per the specific requirements of the study, and in most cases some data will inevitably be missing. In addition, certain variables that have the potential to impact the outcome may not have been recorded at all. Like other sources of clinical data, retrospective data should be identified, appraised and analysed in a systematic way as per sections 8, 9 and 10 of this guidance document.
There are numerous and diverse potential sources of data that can be used in retrospective studies. These include health records, medical insurance databases, patient registries, claims data, laboratory records, pharmacy records, and data previously collected during the normal use of a device. Variations within each of these sources may further increase the heterogeneity of collected data, for example, variations in the structure of patient health records across a health system, heterogenous patient populations within a single database or registry, etc.
Retrospective studies are not considered clinical investigations[footnoteRef:118], and therefore they are not sufficient in themselves for fulfilling the requirement in MDR Article 61(4) to perform a clinical investigation for implantable or Class III devices. Like all sources of device information, data from retrospective sources must be in keeping with the definition in Article 2(48) to be considered "clinical data". This includes a requirement for such data to be generated "from the use of a device" (see Appendix A4 for information regarding clinical data for MDSW). Retrospective studies from the use of the device may be considered as sources of clinical data if they fulfil the definitions of "other studies", "other clinical experience" or "clinically relevant information " as per article 2(48) of MDR and discussed in Sections 8.1.2 - 8.1.4 of this guidance. As with any other source of data, retrospective studies must be appraised and analysed appropriately, as outlined in Sections 9 and 10.
MDCG 2021-6 Rev. 1, Question 18
The following should also be considered when using retrospective studies in a clinical evaluation:
· Aspects to consider from data sources for retrospective studies
The diversity of available data sources has the potential to provide data that more closely resembles the varied and uncontrolled nature of “real world” clinical practice. However, it also provides significant challenges to ensure the data is of sufficient quality.
Challenges in appraising the methodological quality and scientific validity of retrospective studies may be present. These issues may relate to:
· completeness of the data,
· accuracy of the data,
· reliability of the data,
· robustness of the data, and/or
· representativity of the data, including diversity.
Challenges may relate to the appropriateness of the data source to provide data of sufficient quality for the purposes of clinical evaluation. These can include issues related to:
· data protection and governance,
· participant consent,
· technical issues relating to heterogenous sources of data.
The quality of retrospective studies depends heavily on the quality of the data source and data collection tools being used. For example, a well-designed, sustainable registry can be a source of high-quality, relevant, representative data, however many disease registries are not adequately designed to collect device-specific information (such as device model, UDI, serial number etc.). In such an example, while a disease registry may be well-designed for studying the characteristics of a disease, its gaps in device-specific information may hinder the ability to correlate clinical outcomes with specific devices and /or may diminish the quality and usability of the data for the purposes of device evaluation.
· Aspects to consider when reaching conclusions using retrospective studies
In general, data from retrospective studies are of lower quality than data from prospective studies, particularly with respect to the assessment of the device’s clinical performance. Retrospective studies are prone to a number of problems, including:
· confounding by indication (where there is a systemic difference in the characteristics of the groups assessed in the study),
· recall bias (where endpoint data is not systematically collected but is dependent on participants recalling information) and
· missing data (data which may be important in the evaluation of a device may not have been considered important at the time of data collection and therefore may not have been recorded).
Thus, it is generally more difficult to control for confounding variables in retrospective studies. While steps can be taken to minimize the effect of these biases and confounders, some effect will remain. As a result, in general, data from retrospective studies may not be the pivotal source of data in the clinical evaluation of devices.
[bookmark: _Ref164523972][bookmark: _Ref164529648][bookmark: _Ref165303063][bookmark: _Ref166598024][bookmark: _Toc446499062][bookmark: _Ref233808002][bookmark: _Ref233808566][bookmark: _Toc236912941] Relationship between GSPRs and clinical evaluation process
Article 61(1) of MDR requires that the confirmation of conformity with the relevant GSPRs, under normal conditions of use, must be based on clinical data. Therefore, in accordance with Part A of Annex XIV, in the clinical evaluation plan the manufacturer should identify all the GSPRs that potentially require support from clinical data (see subsection Appendix A9.1). Furthermore, Article 61(1) establishes that the evaluation of the acceptability of the benefit-risk profile (see subsection Appendix A9.3) and of undesirable side effects (see subsection Appendix A9.2) as detailed in GSPR 1 and in GSPR 8, respectively, must be based on clinical data that provide sufficient clinical evidence[footnoteRef:119].
MDR, art. 61(1)
This appendix presents an overview of the GSPRs that potentially require clinical data for confirmation of conformity and describes the role of clinical data to support them.
As the requirements span the various stages of the device’s development and lifecycle, having a structured approach to the analysis of GSPRs will make the process more manageable and efficient.
[image: ]A checklist can be a helpful tool when reviewing GSPRs to determine whether clinical data are required. The illustration below is an example of how integrating the question of the need for clinical evidence to confirm conformity into a common GSPRs checklist can help the manufacturer perform this determination.
Note that the above checklist is a suggestion on how a systematic and focused assessment of each requirement may be undertaken. Other methods or tools can be used through this process, provided that the chosen solution enables the manufacturer to have a comprehensive overview of the clinical evidence that is needed to support confirmation of conformity.
GSPRs compliance should be evaluated throughout the device lifecycle. This means that some GSPRs that were not identified as requiring clinical data support at an early stage (e.g., pre-market) may require clinical evidence at a later stage (e.g., post-market).
[bookmark: _Hlk210915260]Once GSPRs which require clinical data for confirmation of conformity have been identified, the methods by which these data will be identified, appraised, analysed and generated should be described in the CEP.
The CER should document the clinical evidence that confirms the conformity of the device with all identified GSPRs (See Section 12 and Appendix A11).
[bookmark: _Ref233282476][bookmark: _Toc236912942]A9.1 General considerations for GSPRs that potentially require clinical data for confirmation of conformity
This section presents general considerations on aspects which may require clinical data to support confirmation of conformity in relation to the
· device safety and performance,
· evaluation of undesirable side-effects, and
· evaluation of the acceptability of the benefit-risk profile for the device.
The table below describes which GSPRs, when applicable, may require clinical data and how often for confirmation of conformity for the device under evaluation, including a non-exhaustive list of aspects to consider. Manufacturers may take this list into account and tailor their approach based on specific characteristics of the device under evaluation.
These elements will support the analysis of relevant clinical data and its documentation in the CER (see Appendix A11).
GSPR
Need confirmation from clinical data?
Rationale/ Example of approach
GENERAL REQUIREMENTS
1
Always.
For all medical devices, clinical data on safety, performance and clinical benefits must exists as per Article 61(1).
GSPR 1 outlines a set of requirements that, if fulfilled, can be expected to allow the conclusion that the device under evaluation is safe and effective. To ensure compliance with GSPR 1, safety and performance need to be prioritised from the earliest stages of design and manufacturing, to prevent potential harm before it happens. Further, manufacturers are required to evaluate the device safety, performance and acceptability of the benefit-risk profile taking into account the SOTA.
In particular, GSPR 1 aspects that may require confirmation of conformity based on clinical data are:
· the device shall achieve the performance intended by the manufacturer
· the device shall be safe and effective
· the device shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons
· any risks which may be associated with the use of the device must constitute acceptable risks when weighed against the benefits to the patient and must be compatible with a high level of protection of health and safety, taking into account the generally acknowledged SOTA.
See also Appendix A9.3 on evaluation of the acceptability of the benefit-risk profile.
2-4
Usually, by relation with GSPR 1.
Throughout the lifecycle of the device, the manufacturer shall apply a risk management system, which establishes a process to assess the acceptability of benefit-risk profile as per GSPR 1.
If a residual risk is not judged acceptable based on the criteria established in the risk management plan, and further risk control measures are not practicable, the manufacturer may need to collect clinical data. For example, for a certain indication or patient population additional clinical data may be needed. The evidence must support the conclusion that the benefits outweigh the residual risks.
5
Usually
Non-clinical testing, which may be based on available standards, may be used to reduce risks related to use error, including risks related to ergonomic features and usability, during device development. However, such testing may not consider all design and usability aspects that may contribute to safety concerns related to use error.
Results from usability evaluations conducted under simulated use conditions may not be fully generalizable to real-world use scenarios and may not identify all potential use errors related to the user interface and human factors. For devices with a user interface, the design may contribute to use errors due to non-intuitive, counter-intuitive or hard-to-learn displays, alarms or controls. The resulting risks may not be fully revealed during simulated usability testing and may only become evident under real-world, time-critical or stressful clinical conditions, or when the device is used infrequently.
Examples include risks related to the ergonomic features of the device, design of user interfaces, the environment in which the device is intended to be used, and the knowledge, experience, education, training and medical and physical conditions of the intended user, all of which may need to require confirming clinical data.
For medical devices intended by the manufacturer for use by the lay population, GSPR 22 should also be considered.
6
Usually
Clinical data may be required to confirm safety and performance over the lifetime of the device, particularly for devices where the interactions of the device with the user or patient may change over time.
Clinical data may be particularly relevant for implantable devices with degradation profiles (e.g., bioresorbable stents), devices that rely on coatings or active substances whose stability may change over time, and drug–device combinations where the durability of both components must be clinically validated. In these cases, clinical evaluation must integrate evidence demonstrating that the benefit–risk profile remains favourable throughout the intended lifetime of the device. Clinical evidence from clinical data may be used to:
- validate the extent of device degradation over time and if it could result in a loss of device performance or compromise the health or safety of the patient or the user or (where applicable) of other persons, with respect to the results from non-clinical tests (see also GSPR 10 and GSPR 13);
- determine potential clinical impact (new clinical conditions or contra-indications) and to identify the information that need to be provided to the users, where the use of a particular substance or processing method in conjunction with a device could limit its lifetime (see also GSPR 10);
- confirm, under clinical conditions, the long-term compatibility between the medical device and the medicinal product(s) concerned, when the device is intended to administer medicinal products. It is expected that both the effectiveness of the medicinal products and the performance of the devices, as outlined in their respective indications and intended use, are maintained as foreseen by the manufacturer. Clinical evidence can confirm this performance during lifetime and clinically validate the compatibility of combination (see also GSPR 12).
7
Occasionally
Conformity is generally demonstrated by non-clinical evidence such as packaging validation, environmental stress testing, and stability studies. Depending on the type of device, the materials, the level of innovation of the technology, or inadequate/inexistent methods to simulate the conditions and impacts, clinical data may be required to address uncertainties as to whether the transport and storage under real-world conditions may affect the device’s characteristics, safety and performance at the point of use.
In particular, for devices sensitive to environmental conditions such as temperature, humidity or vibration, clinical evidence representative of intended use environment may be needed to confirm that performance is not adversely affected during the clinical use.
8
Always.
Evaluating undesirable side effects of medical devices is essential for ensuring patient safety and requires a multi-faceted approach using multiple data sources. See Appendix A9.2. on evaluation of the undesirable side-effects
9
Usually, for devices without a medical purpose included in Annex XVI.
Clinical evaluation of devices without a medical purpose included in Annex XVI shall be based on relevant clinical data concerning safety.
Please see also Commission Implementing Regulation (EU) 2022/2346 and MDCG 2023-6 Guidance on demonstration of equivalence for Annex XVI products.
REQUIREMENTS REGARDING DESIGN AND MANUFACTURE
10
Usually
Chemical, physical and biological properties
Special attention should be given to the need to confirm compliance where the human biological response cannot be fully predicted based on in vitro or animal tests.
For example (not exhaustive), clinical data may be needed in the following cases:
· for certain substances, confirmation of functionality and of the absorption, distribution, metabolism and excretion profile may only be possible through clinical data.
for devices incorporating substances classified as carcinogenic, mutagenic or toxic to reproduction (CMR), or substances with endocrine-disrupting properties, clinical data is generally required to confirm the acceptability of the benefit-risk profile. In such cases, non-clinical data alone may be insufficient to adequately predict the human biological response, particularly with regard to long-term effects, cumulative exposure or use in vulnerable populations. Clinical data should support the justification for the continued use of these substances by demonstrating that the identified risks are adequately controlled and outweighed by the clinical benefits under the intended conditions of use. Clinical evaluation should also contribute to confirming that no suitable alternatives exist (including alternative substances, device designs, manufacturing processes or medical treatments) that would achieve equivalent functionality, performance and a more favourable benefit-risk profile. Where applicable, the clinical evaluation should reflect the latest Commission-mandated scientific guidelines relevant to the substances concerned[footnoteRef:120].
GUIDELINES - on the benefit-risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties - adopted at plenary meeting on 18 June 2019 and updated 14 june 2024 – SCHEER
11
Occasionally
Infection and microbial contamination
While sterility validation, microbiological testing and conformity with relevant standards generally support conformity with GSPR 11, clinical data may be relevant and necessary to confirm conformity in real use. In particular, for long-term invasive devices, reusable devices, or devices used in high-risk patient populations, clinical evidence may be needed to confirm that the device does not lead to infection or microbial contamination beyond what is predicted in non-clinical assessments.
In the case of reusable devices, aspects related to reprocessing (e.g., cleaning, disinfection and sterilization) require particular attention. For example, where the maximum number of reuse cycles is determined using simulated conditions, additional clinical data may be required to confirm that these limits remain adequate under routine clinical use and to verify that repeated real-world reprocessing does not lead to an increased risk of infection or microbial contamination.
12
Usually
Devices incorporating a substance considered to be a medicinal product and devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body.
For devices incorporating a substance considered to be a medicinal product, clinical data may be required to confirm the safety and usefulness of a medicinal product as a part of the device, in addition to clinical data on the device under evaluation to confirm its safety and performance.
For devices composed of substances or combinations of substances that are absorbed by or locally dispersed in the human body, where non-clinical data are insufficient to fully characterise human exposure, clinical data on absorption, distribution, metabolism and excretion, toxicity, interactions and local tolerance, would be needed, as applicable.
Clinical evaluation should reflect the applicable requirements of Directive 2001/83/EC and take into account relevant scientific guidelines issued by the European Medicines Agency, with any deviations appropriately justified[footnoteRef:121].
The consultation of a medicinal products authority required under GSPR 12 and Annex IX (Section 5.2) or Annex X (Section 6) of Regulation (EU) 2017/745 typically involves the assessment of clinical data to support the safety and usefulness of the medicinal substance when incorporated in a medical device.
13
Occasionally
Devices incorporating materials of biological origin
For devices incorporating materials of biological origin, including non-viable tissues or cells of human or animal origin or other non-viable biological substances, compliance with GSPR 13 is primarily supported by non-clinical data addressing the safety of the materials, including validated methods for the elimination or inactivation of transmissible agents.
Requirements set out in Directive 2004/23/EC and Directive 2002/98/EC, or in Regulation (EU) 722/2012, as applicable, should be addressed, as applicable.
However, clinical data may be required where residual risks remain or where non-clinical data alone are insufficient to confirm the acceptability of the overall benefit-risk profile.
For example, clinical data may be required in the following cases.
· For devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable, in accordance with Directive 2004/23/EC any serious adverse reaction observed during or after clinical application that may be linked to the quality or safety of tissues or cells, where identified, shall be taken into account in the clinical evaluation.
· For devices manufactured using non-viable animal tissues or derivatives rendered non-viable referred to in Regulation (EU) No 722/201, manufacturer must justify, the decision to use such materials, including a rationale for the acceptability of the overall transmissible spongiform encephalopathy (TSE) risk estimate. This justification should take into account the expected clinical benefit, potential residual risk and suitable alternatives, such as lower risk tissues or synthetic alternatives. Clinical data may be necessary to support the confirmation of the expected clinical benefit.
· For all devices incorporating tissue of biological origin, where the implementation of elimination or inactivation methods may lead to degradation of the material that may compromise the clinical benefit, performance or functionality of the device, clinical data are expected to support the assessment of the clinical impact of such degradation. Clinical evaluation should address whether the resulting residual risks are acceptable in view of the intended purpose and the expected clinical benefits.
14 - 16
Occasionally
Construction of devices and interaction with their environment
When the device is used in combination with other devices or equipment, the whole combination, including the connection system, shall not impair the specified performance of devices nor cause negative/unfavourable medical manifestations due to negative interactions, unwanted reciprocal interference or complex interoperability during combined use. For example, for devices used in complex hospital settings, or in home environments where conditions are less controlled, clinical evidence may be necessary to confirm that device construction does not lead to unexpected safety or performance issues.
Devices with a diagnostic or measuring function
For these devices, clinical data may be needed to confirm accuracy and reproducibility when used as intended.
The following list gives examples of performance aspects that may be relevant to diagnostic devices and that, where relevant, may require supportive clinical data:
reproducibility of independent acquisition of images (same patient, same machine, different user);
reproducibility of independent reporting of images (same patient, same machine, same images, different user);
diagnostic sensitivity and specificity of the test for major indications; positive and negative predictive values of the test;
comparisons of performance of new iterations of diagnostic software against previous software versions;
normal values by age and gender, reflecting the groups in which the diagnostic system may be used.
A similar approach may be taken for devices with a measuring function.
Protection against radiation
Clinical data may be required where the exposure of patients or users to ionising or non-ionising radiation cannot be fully characterised under non-clinical conditions. For example, for diagnostic imaging or therapeutic devices, clinical data may be necessary to confirm that radiation levels remain within recommended safe limits during clinical use, including repeated or long-term exposure.
17-18
Usually
Electronic programmable systems/Active devices and devices connected to them
For medical devices incorporating electronic programmable systems, including software and software that are medical devices in themselves, clinical data may be required where uncertainty remains regarding the potential impact of software behaviour, user interaction or cybersecurity risk control measures or other issues may have on patient safety or clinical performance in clinical use. This is particularly relevant where the system directly supports or drives therapeutic or diagnostic decisions. Where such risks cannot be fully assessed through bench testing alone, clinical data may be necessary to confirm safety and performance when used as intended.
Some examples when clinical data may be required include (list not exhaustive)
- when performance has been validated on controlled datasets which cannot reliably predict accuracy across diverse patient populations and when variable inputs (such as image quality) may be encountered in clinical use.
- when bench validation has confirmed correct dosing algorithms, but the interaction between the user interface, alarm systems and clinical workflows, needs to be confirmed by clinical data to ensure that it does not result in dosing errors.
- to confirm that the device output is correctly interpreted and used by the intended users, and that the algorithms perform as intended and meet the intended purpose.
For further information on clinical data for medical devices software see Appendix A4.
19
Occasionally
Active implantable devices
For implantable medical devices, clinical investigations, which will generate clinical data, are mandatory as per Article 61(4), with the applicable exemptions[footnoteRef:122]. Some aspects that may require support from clinical data include the characteristics of the patient population the effect of physical activity or ageing on implant performance, the expected lifetime of the implant, the reversibility of the implantation, whether the implant can be modified or configured while implanted and the access connection to perform this modification or configuration (e.g. physical access point or wireless connection to the implanted medical device).
Please see MDCG 2023-7 for more information on exemptions.
20-21
Occasionally
Protection against mechanical and thermal risks
Protection against the risks posed to the patient or user by devices supplying energy or substances
While non-clinical testing is generally the primary means to demonstrate conformity, manufacturers should be aware that clinical data may be required to confirm where residual uncertainties remain regarding whether test conditions, test methods or acceptance criteria adequately reflect real-world clinical conditions. In particular:
· for implantable or long-term use devices, devices that generate or dissipate heat, or devices exposed to variable mechanical loads depending on patient-specific factors [GSPR 20], or;
· devices that deliver energy or substances directly into the human body, where variables such as tissue response, absorption, distribution, or unintended effects on adjacent structures may not be fully captured through bench or preclinical testing [GSPR 21]
clinical data should confirm that the relevant safety requirements are met in practice.
The confirmation of conformity to these GSPRs could be also related with ergonomic features (in this case may be combined with GSPR 5).
22
Usually.
Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons
For devices for use by lay persons, clinical data may be necessary to confirm usability, safety, and performance under real conditions of use. For example, clinical data may be useful to confirm that instructions for use are clear, that the device can be handled correctly by lay persons, and that potential risks related to variations in use are minimized.
Moreover, where appropriate, the manufacturer shall include a procedure by which the lay person can verify, at the time of use, if the device performs as intended by the manufacturer. Clinical data may be necessary to determine if such procedure is correct.
REQUIREMENTS REGARDING THE INFORMATION SUPPLIED WITH THE DEVICE
23
Usually
The information provided in the IFU or labelling (e.g. intended purpose, expected clinical benefits, residual risks, side effects, warnings, precautions, contraindications, guidance on how the user is expected to act to in predictable abnormal situations, alarms or use-related issues during operation instructions for managing foreseeable unwanted situations) should be supported by sufficient clinical evidence and be consistent with the clinical evaluation.
[bookmark: _Ref233282534][bookmark: _Toc236912943]A9.2 Evaluation of the undesirable side-effects
GSPR 8 requires that any undesirable side-effect[footnoteRef:123] [footnoteRef:124] must constitute an acceptable risk when weighed against the intended benefits.
For the purpose of this guidance, an ‘undesirable side-effect’ under the MDR should be understood as any unintended and unwanted medical manifestation in the human body, as a consequence of the normal use of a device. Undesirable side-effects are not the result of a malfunction, deterioration in the device’s characteristics or performance, or an inadequacy in the information supplied by the manufacturer but rather they are associated with an adverse reaction by the patient to a device that is working properly. An unsuccessful treatment (or treatment failure) should not be considered an undesirable side effect. More details on this understanding are in the MDCG 2023-3.
It should be noted that the terms ‘undesirable side-effects’ and ‘side-effects’ are used synonymously in the MDR.
Undesirable side-effects can be expected or unexpected[footnoteRef:125]:
Considered as incidents under the MDR (Article 2(64) MDR). For further information please consult guidance on Post-Market Surveillance and Vigilance (PMSV)
· expected undesirable side-effects must be clearly documented in the instructions for use and indicated and quantified in the manufacturer’s technical documentation
· unexpected undesirable side-effects are not considered a priori in the manufacturer’s risk analysis, quantified in the manufacturer’s technical documentation or documented in the product information. If unexpected undesirable side-effects occur, they are to be handled like all incidents, which means that a (re)evaluation of the acceptability of the risks, and the amount of clinical evidence to balance the risks could be necessary.
In order to evaluate the acceptability of an undesirable side-effect:
· there needs to be clinical data for the evaluation of the nature, severity and frequency of potential undesirable side-effects
· the clinical data should contain an adequate number of observations to support the conclusions relating to undesirable side-effects and the benefits of the device
· consideration has to be given to the SOTA (see Appendix A1).
If there is insufficient clinical evidence due a lack of clinical data or an insufficient number of observations, conformity with the requirement on acceptability of undesirable side-effects is not fulfilled.
[bookmark: _Ref233282512][bookmark: _Toc236912944]A9.3 Evaluation of the acceptability of the benefit-risk profile
It is expected,
· that the clinical evaluation demonstrates that any known and foreseeable risks which may be associated with the intended purpose, and any undesirable side-effects, are minimised and acceptable when weighed against the benefits and are compatible with a high level of protection of health and safety, during normal conditions of use; and
· that the IFU (where applicable) include the clinical benefits to be expected as well as correctly describe the intended purpose of the device as supported by sufficient clinical evidence; and
· that the IFU (where applicable) contain correct information to reduce the risk of use error, information on residual risks and their management as supported by sufficient clinical evidence (e.g. handling instructions, description of risks, warnings, precautions, contraindications, guidance on how the user is expected to act to in predictable abnormal situations, alarms or use-related issues during operation,).
It is not possible to directly weigh one benefit against one risk because the risks and benefits vary in magnitude and number. Therefore, the overall benefits should be compared to the overall risks.
When evaluating the acceptability of the benefit-risk profile, it is important to look for clinical data on benefits and risks. The benefits and risks should be measurable and the benefit-risk ratio acceptable for the various indications and intended purpose(s) of the device when compared with parameters based on SOTA in medicine. If the benefit-risk ratio is not acceptable for all clinical indications and intended purpose(s), these should be reconsidered and limitations should be applied to them.
[bookmark: _Hlk140159575]The risk management documents are expected to identify the risks associated with the device and how such risks have been addressed. The clinical evaluation is expected to continually address the significance of any risks that remain after risk mitigation strategies have been employed by the manufacturer, and to ensure that the benefit-risk ratio remains acceptable over time, taking into account the SOTA.
Positive impacts of a device on the health of an individual should be meaningful (clinically relevant) and measurable. The nature, extent, probability and duration of benefits, where applicable, should be considered. Benefits may include:
· positive impact on clinical outcome such as reduced mortality, morbidity or improvement of impaired body function,
· the patient's quality of life (significant improvements, including by simplifying care, improving body functions, providing relief from symptoms),
· clinical management of patients, such as high throughput and increasing automation addressing workforce shortages thereby providing timely access to care,
· outcomes related to diagnosis (such as allowing a correct diagnosis to be made, providing earlier diagnosis of diseases or specifics of diseases, or identifying patients more likely to respond to a given therapy),
· positive impact from diagnostic devices on clinical outcomes, or
· public health impact (such as to the ability of a diagnostic medical device to identify a specific disease and therefore prevent its spread, or to identify phases, stages, location, severity or variants of disease, predict future disease onset).
The data may show that a benefit may be experienced only in a subset of patients in the target population, or, on the other hand, that a benefit can be extrapolated throughout the target population. It is also possible that the data will show that different patient subgroups are likely to experience different benefits or different levels of the same benefit. A large benefit experienced by a small proportion of subjects may raise different considerations than a small benefit experienced by a large proportion of subjects. For example, a large benefit, even if experienced by a small population, may be significant enough to outweigh risks, whereas a small benefit may not, unless experienced by a large population of subjects.
Where possible, benefit(s) are often evaluated along a scale or according to specific endpoints or criteria (types of benefits), or by evaluating whether pre-identified clinical outcome parameters were achieved. The change in patients/users’ condition or clinical management as measured on that scale, or as determined by an improvement or worsening of the endpoint, may determines the magnitude of the benefit(s) in patients/users. Variation in the magnitude of the benefit across a population may also be considered. Ideally, these parameters should be directly clinically relevant.
In certain cases, benefits can be assumed when validated surrogate endpoints are met (such as obtaining certain results with diagnostic devices or measurements of anatomical or physiological properties). Based on the current state of medical knowledge, the manufacturers shall justify and document the clinical relevance of endpoints used for the clinical evaluation of a device and demonstrate the validity of all surrogate endpoints (if surrogate endpoints have been used). See Section 9.3.1.1 for further information on the use of surrogate endpoints.
Conversely, negative impacts/risks of a device on the health of an individual should also be considered especially those not predictable. New risks/harms, or new data regarding identified risks, including the ones already assumed as mitigated, could be gathered from:
· adverse events/ serious adverse events, device deficiencies or incidents identified during clinical/PMCF investigations
· incidents and serious incidents, as defined in MDR Article 2(64) and 2(65) respectively (even predictable device-related incidents on the basis of the mode of action of the device)
· estimates of the incidence of incidents
· other real-world data form the post-market phase, including for example complaints, incidents, installed base surveillance, PMCF studies, register analysis and surveys
It is also important to look at the foreseeable sequences of events associated with the device that can result in hazardous situations, which can result in harm. The number of different types of hazardous situations and harm that can potentially result from using the device and the severity of their aggregate effect has to be considered. When multiple harmful events occur at once, they have a greater aggregate effect.
Manufacturer must monitor devices safety and performance in clinical use and implement measures to verify clinical benefit-risk profile in the clinical evaluation if there are significant changes on the device or new information available that could potentially impact the clinical benefit-risk profile of the device. New information could relate, for example, on significant changes on the SOTA, or risks identified in the PMS and product risk analysis.
[bookmark: _Ref233808176][bookmark: _Ref233808329][bookmark: _Ref233808408][bookmark: _Toc236912945]How to specify and justify the level of clinical evidence necessary
A key goal of the clinical evaluation process is to determine whether the relevant clinical data provides sufficient clinical evidence as a basis for:
· the confirmation of conformity with the relevant GSPRs under the normal conditions of the intended use of the device,
· the evaluation of the undesirable side-effects, and
· the acceptability of the benefit-risk profile for the device[footnoteRef:126].
Per MDR Article 61(1)
To achieve this goal, the evaluators need to have an appropriate understanding of what level of clinical evidence is necessary to demonstrate conformity with the relevant GSPRs for their device. As per Article 61(1), this must be specified and justified by the manufacturer, and the specified level must be appropriate in view of the characteristics of the device and its intended purpose.
Manufacturers should specify and justify the necessary level of clinical evidence as part of clinical evaluation planning (Stage 0), against which the clinical data should be analysed during Stage 3. This should be re-evaluated periodically as part of the continuous clinical evaluation process, to allow for the level to be adjusted in light of new information (such as new developments in the SOTA, new guidance from expert panels, relevant new risks identified from the manufacturer’s risk management system, etc.)
When specifying the necessary clinical evidence, the manufacturer should take into account the following aspects, as it relates to their device:
· Relevant information described in the clinical evaluation plan, including
· The GSPRs that require support from relevant clinical data (see Appendix A99)
· The intended purpose of the device
· The intended target groups, indications, and contra-indications
· The intended clinical benefits to patients and specified clinical outcome parameters
· The specified methods for examination of clinical safety including residual risks and potential undesirable side effects
· The generally acknowledged SOTA including currently available alternatives, if any[footnoteRef:127], see Appendix A1
Per MDR Article 61(3)(c)
· The specified parameters to determine, based on the SOTA, the acceptability of the benefit-risk profile for the various indications and intended purpose
· An indication of how benefit-risk issues relating to specific components such as use of pharmaceutical, animal or human tissues are to be addressed, where present
· The clinical development plan.
· Other relevant characteristics of the device, including, where applicable, the:
· Duration and frequency of use
· Invasiveness of the device
· Expected lifetime of the device
· Novelty of the device or related clinical procedure
· Range of devices/ models/ sizes/ settings to be covered by the evaluation
· Materials incorporated into the device, with particular attention to:
· Any substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’) and substances having endocrine-disrupting properties (ED)
· Any medicinal substance, including a medicinal product derived from human blood or human plasma
· Any tissues or cells of human or animal origin or their derivatives, which are non-viable or rendered non-viable.
· Any relevant known and foreseeable risks associated with use of the device
· Any relevant non-clinical data, if used in accordance with section 8
· Any specific requirements that may apply to the device in question, including
· Required clinical investigations per MDR Article 61(4)-(6), see MDCG 2023-7
· Well-established technologies per MDR Article 61(8), see MDCG 2020-6
· Products listed in Annex XVI per MDR Article 61(9)
· Where demonstration of conformity with GSPRs based on clinical data is deemed not appropriate per MDR Article 61(10)
· Where clinical evaluation is intended to be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated per MDR Annex XIV section 3, see MDCG 2020-5.
· Any other relevant guidance or standards that may apply to the device, including
· Orphan devices and breakthrough devices, see Appendix A11
· Custom made devices
· Devices manufactured in a healthcare institution
· Legacy devices
· Relevant harmonised standards, common specifications, other MDCG guidance, or appropriate expert consensus clinical guidance, if any
· Any relevant views expressed by an expert panel, if consulted in line with MDR Article 61(2).
In general, the specified level of clinical evidence needed must be appropriate in view of the characteristics of the device and its intended purpose. To that end, it should be proportionate to the risk associated with the use of the device. The level should be sufficient to be reasonably likely to identify and evaluate undesirable side-effects and risks throughout the expected lifetime of the device. The intended clinical benefits should also be considered, and the clinical evidence must be sufficient to confirm that the benefit-risk ratio is acceptable throughout its expected lifetime, when compared against the SOTA including currently available alternative treatment options, if any.
Where appropriate, the level of clinical evidence needed should be specified for each indication, with respect to the confirmation of safety and clinical performance, and the evaluation of side-effects and the acceptability of the benefit-risk profile. The level of clinical evidence needed should duly consider, as applicable, any harmonised standards and common specifications, while also taking into consideration other relevant sources of information such as expert panel opinions, guidance, non-harmonised standards, and scientific literature, in the context of the SOTA.
Once clearly defined, these specifications can act as the level to which the clinical data for the device should be compared during clinical evaluation, and in particular during analysis (see Stage 3). If, following analysis, the evaluators can demonstrate and justify that the available clinical data meet these specifications, then it may be considered that sufficient clinical evidence has been provided for the purposes outlined in MDR Article 61(1). If the available clinical data do not fully meet the specified level of clinical evidence needed, then the manufacturer will need to generate additional clinical data focused on the aspects that have not been met, see Stage 4.
Updates to determination of clinical evidence needed
As part of the continuous clinical evaluation process, it is expected that the manufacturer’s specification of the level of clinical evidence needed is re-evaluated at appropriate periods. This is particularly relevant for devices that undergo changes in design or manufacture after placement on the market, (e.g., new models or iterations, or changes in response to vigilance reports or market surveillance). Special attention should be given to the following aspects with respect to their potential impact on the clinical evidence needed for the device, where relevant:
· new design features, including new materials and ergonomic features
· new intended purposes, including new indications, new target populations (age, sex, etc.)
· new claims the manufacturer intends to use
· new types of users (e.g. lay persons)
· new risks associated with the device
· changes to the invasiveness, duration of use, or numbers of re-applications
· changes to the SOTA including any changes or emergent issues related to available alternative treatment options if any
· Any new relevant guidance, harmonised standards, or common specifications that may have been published since the previous clinical (re-)evaluation as part of the continuous clinical evaluation process.
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[bookmark: _Toc236912946]Clinical evaluation report - proposed table of contents, examples of contents
The creation and updating of a CER is a crucial requirement of MDR for the confirmation of conformity with relevant GSPRs.
The CER should be developed by the manufacturer as a standalone document and includes all the relevant information and the analysis required to provide evidence for the confirmation of conformity with relevant GSPRs. The inclusion of data which does not directly support this analysis should be avoided. Detailed source of data should be provided as annexes to the CER (e.g. full copy of publications, full list of literature search results, clinical investigation plan and report, both for the device under evaluation and the equivalent device (if any), etc.).
The content of the table below is for illustration and further elements may be relevant. The content of the clinical evaluation report will vary according to the lifecycle phase, technology and history of the device under evaluation.
Table of contents
Examples
1. Summary
Executive summary.
This section should provide a concise executive summary focusing on the relevant aspects of clinical evaluation report to the notified body and/or regulatory authorities.
It should provide a summary of the information on the clinical data[footnoteRef:128] supporting the clinical evidence[footnoteRef:129] for the confirmation of conformity with relevant GSPRs, including whether the clinical evaluation is based on clinical data of the device under evaluation and/or an equivalent device, the determination of the benefit-risk profile in the intended target groups and medical indications, and the demonstration of acceptability of that profile based on the SOTA in the medical field concerned.
Article 61 (11) and Article 2 (48) of the MDR
Article 2 (51) of the MDR
2. Scope of the clinical evaluation and device under clinical evaluation
Key information necessary to understand the context of the clinical evaluation, particularly useful for the notified body and/or the regulatory authorities, related to the clinical evaluation (reflecting the CEP elements - See Section 7).
Device description, as indicated in Appendix A2.
Applicable standards and guidance documents.
If equivalence is claimed, an identification of the equivalent device(s) (by name and Basic UDI-DI if available, together with the name(s) of its/their manufacturer(s) and a description of how the equivalence has been demonstrated.
Whether the device is already CE marked and since when, or where it is available on a market outside the EU and since when.
History of the device, including information on the regulatory history, whether it is a new device or a device developed by modifications of a previous version of the device, date of past modifications with reasons and description, and also a summary of sales volumes.
Changes since the last report, whether the device has been modified, models, sizes, software, accessories, new intended purposes, new claims, new events related to the device with an impact on the clinical evaluation. Identification of the sections of the clinical evaluation report that are concerned with the new information and have been modified.
3. SOTA, including clinical background,
Description of the state of art (see Appendix A1) or a summary of key elements if the full description is reported in the CEP or in a separate document.
4. Clinical evaluation overview
4.1. Type of clinical evaluation
Description of whether- the clinical evaluation is based on clinical data of the device under evaluation and/or an equivalent device
or
if demonstration of conformity with GSPs based on clinical data is not deemed appropriate.
4.2. Demonstration of equivalence (only when equivalence is claimed)
See MDCG 2020-5 for more information on the demonstration of equivalence.
Identification of the equivalent device and its manufacturer. Exact name, models, sizes, software versions, accessories, etc.
Relationship between the device under evaluation and the device for which equivalence is claimed (e.g. the device under evaluation has been designed by modifications of a device already marketed by the same manufacturer or by other manufacturer, other).
If modifications were introduced to address specific safety and/or performance issues, the manufacturer should demonstrate that there are no additional risks or potential of negatively altered performance related to the introduced modifications, or describe how the benefits of the device outweighs them.
Comparison of technical, biological and clinical characteristics from the device under evaluation with those from the equivalent device, which shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device under evaluation[footnoteRef:130] (see MDCG 2020-5 for details). A gap analysis should be conducted by the manufacturer to evaluate any clinically significant difference(s).
Section 3, Part A, Annex XIV of the MDR
It shall be clearly demonstrated that manufacturers have sufficient level of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence (see Appendix II of MDCG 2023-7 for more information).
Justification of equivalence, based on proper scientific data, description of relevant technical, biological and clinical characteristics that affect clinical properties of the device, differences between the intended medical purpose of the device under evaluation and the equivalent device (indications, contraindications, precautions, target patient groups, target users, mode of application, duration of use/ number of re-applications, others), type of device-body interaction.
If the manufacturer identifies more than one equivalent device to the device under evaluation, the justification of equivalence for each device shall be presented based on proper scientific data for all relevant characteristics: technical, biological and clinical.
A manufacturer of a medical device shall not claim equivalence to different parts of different devices.
A manufacturer of a medical device shall not claim equivalence to a product without an intended medical purpose listed in MDR Annex XVI. However, in case of products without an intended medical purpose listed in MDR Annex XVI, the manufacturer may claim equivalence to an analogous medical device if duly justified (see MDCG 2023-6).
Comparative tabulations for the device under evaluation versus the equivalent device showing parameters relevant to the evaluation of the three characteristics. Comparative drawings or pictures of the device and the equivalent device showing the elements in contact with the body.
Identification of differences, evaluation if differences are expected or not to influence the clinical performance and clinical safety of the device, reasons for assumptions made.
Conclusions concerning equivalence. Whether the comparison carried out covers all products/ models/ sizes/ settings/ accessories and the entire intended purpose of the device under evaluation, or only certain products/ models/ sizes/ settings/ accessories, or selected aspects of the intended purpose, which ones.
Conclusion on whether equivalence is demonstrated; if it is demonstrated, confirmation that any identified differences are not expected to affect the clinical performance and clinical safety of the device under evaluation; description of any limitations and gaps.
4.3. Results of the risk management activities
4.4. Clinical data generated and held by the manufacturer
The risk management documents of the device, e.g. the hazard identification list, risks identified from the risk analysis. The risk management documents are expected to identify the risks associated with the device and how such risks have been addressed. The clinical evaluation is expected to address the significance of any risks that remain after design risk mitigation strategies have been employed by the manufacturer.
See Section 8.3 on clinical data generated and held by the manufacturer.
Note that for class III and implantable devices, when clinical investigation is not performed by virtue of paragraph 61(6), a justification shall be provided (see MDCG 2023-7 for further guidance).
4.5. Clinical data from literature
See Section 8.4 and Appendices A5-A6.
Brief summary and justification of the literature search strategy applied for retrieval of clinical data, including objectives, sources used, search questions, search terms, selection criteria applied to the output of the search, quality control measures, results, number and type of literature found to be pertinent.
4.6. Summary of relevant clinical data
Summaries of clinical data generated and held by the manufacturer and of scientific literature found to be pertinent, including brief summary of the studies with references (methods, results, conclusion of the authors). Grouping of relevant clinical data in pivotal and supportive is recommended.
Below there is an example of how to present the summary of the relevant clinical data:
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4.7. Appraisal of relevant clinical data
4.8. Analysis of the relevant clinical data in relation to relevant GSPRs
See Section 9 and Appendix A7.
Summarises the criteria used by the evaluators for appraising data sets (i.e. the appraisal plan).
References to the detailed appraisal plan in the CEP or in a separate document.
Presents, for each data set, the appraisal output, that is the scientific validity of contents, the relevance to the clinical evaluation, weighting attributed to the data, contents used (performance data, safety data, both), reasons for rejecting a study or document, reasons for rejecting some of its contents.
Below there is an example of how to present the appraisal of the relevant clinical data. Relevant clinical data sets summary and their appraisal, could also be presented in the same table as follows:
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4.8.1. Requirements on safety
See Section 10 and Appendix A9.
Summary of conformity assessment with requirements in relation to safety.
Description of:
· quantitative and qualitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects.
· whether there are specific design and manufacturing features that pose safety concerns identified in the device risk management documentation that require evaluation from a clinical perspective, and whether these have been adequately addressed.
· whether the risks identified in literature have been adequately addressed.
· whether all the hazards and other clinically relevant information (e.g. clinical precautions for reduction of risks, clinical management of risks) have been identified appropriately.
· whether the safety characteristics and intended purpose of the device requires training of the end-user or other precautions, if users foreseen are adequately qualified, if training requirements and other warnings, precautions, contra-indications are described in the information materials supplied by the manufacturer which should be reviewed to ensure they are consistent with the relevant clinical data appraised in stage 3 and that all the hazards, information on risk mitigation and other clinically relevant information have been identified appropriately.
· special safety concerns about the risk related to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety) and also related to the stresses which can occur during the lifetime of the device (such as in case of reusable devices).
· the quality, safety and usefulness of the ancillary action of the medicinal substance or the ancillary non- viable animal or human tissues, are incorporated in the medical device.
· the safety (in particular safety with regard to viruses and other transmissible agents) for patients, users and, where applicable, other persons of the medical devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable covered by MDR[footnoteRef:131], tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable or other non-viable biological substances, in order to guarantee the benefit and needed biologic safety.
Article 1(6) (g) of the MDR
· whether there is sufficient clinical evidence for determining the safety of the device.
· whether there is consistency between the SOTA , the available clinical data, the information materials supplied by the manufacturer, and the risk management documentation for the device.
4.8.2. Requirements on performance
See Section 10 and Appendix A9.
Summary of conformity assessment with requirements in relation to performance.
Description of clinical performance. For each intended clinical performance, extent to which evaluation of benefits is possible based on available data, limitations of the data, description of gaps, uncertainties or unanswered questions, and assumptions, taking into account the clinical outcome parameters defined in the CEP. Whether there is sufficient clinical evidence for every intended clinical performance.
4.8.3. Requirement on acceptability of side-effects
See Section 10 and Appendix A9 (in particular Appendix A9.2)
Summary of conformity assessment with requirement in relation to the acceptability of undesirable side-effects.
Whether the clinical data available is of sufficient amount and quality for the detection of potential undesirable side-effects, their severity and frequency, limitations of the data, description of gaps, uncertainties or unanswered questions, and assumptions.
Whether the undesirable side-effects are acceptable and corresponding justifications taking into consideration the SOTA..
4.8.4. Requirement on acceptability benefit-risk profile
See Section 10 and Appendix A9 (in particular Appendix A9.3) Summary of conformity assessment with requirement in relation to the acceptable benefit-risk profile.
Summary of the total experience with the device, including estimated numbers and characteristics of patients exposed to the device in clinical investigations, PMCF, from other user experience, and in the market; duration of follow-up.
Nature, extent/severity, probability/frequency, duration of benefits to the patients and of undesirable side-effects and other risks.
For the various indications and the intended purpose or purposes of the device, whether the benefit-risk profile, including its uncertainties or unanswered questions, is compatible with a high level of protection of health and safety, taking into consideration the parameters determined in the plan and the SOTA in medicine..
Relevant aspects to consider:
· Evaluation of the description of the intended purpose of the device
· Evaluation of the device’s benefits to the patient
· Quantification of benefit(s) to the patients
· Evaluation of the l risks of devices
· Evaluation of acceptability of the benefit-risk profile.
Also, additional aspects in evaluation of acceptability of the benefit-risk profile in certain medical devices, such as devices that incorporate substances which are carcinogenic, mutagenic or toxic to reproduction (CMR) and substances having endocrine-disrupting properties (ED), tissues or cells of animal or human origin, or their derivatives, which are non-viable or rendered non-viable.
5. Conclusions
See Section 12.
Clear statement concerning compliance to the GSPRs set out in Annex I MDR.
Assessment of whether the CER is in keeping with the CEP and justification of any deviation. Acceptability of the benefit-risk profile according to the SOTA in the medical fields concerned and according to available medical alternatives.
Adequacy of the information materials supplied by the manufacturer, whether the intended purpose and risk reduction measures are adequate; discrepancies.
Suitability of the device, including its IFU, for the intended users and usability aspects; discrepancies.
Adequacy of claims foreseen by the manufacturer; discrepancies.
If there is consistency between the clinical data, the information materials supplied by the manufacturer, the risk management documentation for the device under evaluation; discrepancies.
Whether there is consistency between these documents and the SOTA; discrepancies.
Description of residual risks and uncertainties or unanswered questions, whether these are acceptable for CE-marking, how these should be followed during PMS (uncertainties regarding medium- and long-term performance, safety under wide-spread use, residual risks such as undesirable side-effects and complications occurring at rates below detection possibilities of currently available clinical data, others). Whether these are already being addressed in ongoing PMS activities, e.g. in currently ongoing PMCF studies. Whether new or additional PMS activities, including PMCF studies, should be foreseen.
6. Date of the next clinical evaluation
See Section 14. Suggested date, with justification.
7. Dates and signatures
See Section 12.
Date of the clinical evaluation report.
Statement that the evaluators agree with the contents of the report. Dates, names and signatures of the evaluators.
Final release by the manufacturer. Date, name and signature according to manufacturer’s document control procedures.
Please note that electronic signatures are accepted
8. Qualification of the responsible evaluators
See Section 6.4.
9. [bookmark: _Ref233282663]References
Appropriate references to related documents should be supplied as discussed in Section 12.
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[bookmark: _Toc236912947]Proposed checklist for the release of the clinical evaluation report
It is recommended to check the following aspects for the release of a clinical evaluation report:
· is the CER a standalone document and does it include an executive summary which provides an overview on the relevant aspects of clinical evaluation of the device?
· can the report be read and understood by a third party, does it provide sufficient detail for understanding the clinical evaluation procedure adopted by the evaluators, the data that are provided, all assumptions made and all conclusions reached?
· is all the relevant information regarding the device description covered by the CER? For additional information, see Appendix A2.
· is key information necessary to understand the context of the clinical evaluation as outlined in the CEP reflected in the CER?
· if the device is already marketed in the Union or outside the Union, have the latest PMS/ PMCF data been taken into consideration and have these been summarised and referenced in the CER (See also Section 8.1.4)?
· are all clinical data mentioned, adequately summarised and appraised in the CER?
· if equivalence is claimed,
· is the equivalent device clearly identified as well as its manufacturer?
· is demonstration of equivalence between the device under evaluation and equivalent device(s) included in the report (considering the technical, biological and clinical characteristics)?
· does the report disclose all the differences between the device under evaluation and the equivalent device? Does it explain why the differences are not expected to significantly affect the clinical performance and clinical safety of the device?
in respect to the SOTA,
· when updating the CER, has the information on SOTA been updated as well?
· is SOTA described (see Appendix A1) or are its key elements summarised (if the full explanation is reported in the CEP or in an appendix)? Is it adequately substantiated by literature?
· does the content of the CER fully correspond to the SOTA?
· does the report explain why the benefit-risk profile and the undesirable side-effects are acceptable (including the nature, severity, probability and duration of acceptable harm) in relation to the SOTA (including information on available diagnostic or therapeutic alternatives, historical context and developments, etc.)?
· If the CER covers several models/ sizes/ settings and/or different medical conditions, is there sufficient clinical evidence and are the report’s conclusions correct for
· all the devices?
· all its sizes, models and settings? (Including the smallest/ largest size, highest/ lowest dose, etc.)
· every indication (as described in the IFU/ not excluded with contraindications in the IFU)?
· the entire target population (pre-term infants to old age, for males and females, etc., if not restricted in the IFU)?
· every form, stage and severity of the medical condition, as applicable (Including the most severe/ most benign forms, acute/ chronic stage, if not excluded in the IFU)?
· all intended users (including lay persons, if not excluded in the IFU, and any unusual user group)?
· the whole duration of device use, including the maximal number of repeated exposures (as indicated by the IFU)?
· if there are any discrepancies as to the above, are they identified in the report’s conclusions?
· is conformity to each of the relevant GSPRs clearly stated and are all discrepancies identified in the report’s conclusions?
· are all the quantitative and qualitative qualitive aspects of clinical safety described and are all the risks that could have a significant impact on the benefit-risk analysis identified and assessed in the CER?
· are the clinical benefits, in relation to relevant clinical outcome parameters, properly described and assessed?
· do the report’s conclusions include the relevant information about all the risks that could have a significant impact on the benefit-risk analysis' been identified in the clinical evaluation? Is there alignment between the risk management and clinical evaluation?
· do the information materials supplied by the manufacturer correspond with the contents of the CER and are all discrepancies identified and justified in the report’s conclusions?
· do the report’s conclusions identify all residual risks and uncertainties or unanswered questions that should be addressed with PMS / PMCF activities?
· do the report’s conclusions support the intended purpose, the claims and the information material supplied by the manufacturer and SSCP?
· do the report’s conclusions demonstrate a sufficient level of clinical evidence to demonstrate compliance with the relevant GSPRs?
· is the report dated, and includes information about next CER update (date and justification)?
· is the qualification of the evaluators included in the report and does it include the aspects listed in section 6.4?
· does the manufacturer hold a CV of each of the evaluators and are these up to date?
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13.08.2026
Datei
PD
