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Rapid HTA report
Flash Glucose Monitoring Systems
for diabetes subjects in insulin therapy
February 2018
This report should be cited as: Lo Scalzo A, Abraha I, Bonomo MA, Chiarolla E, Migliore A,
Paone S, Toni S, Cerbo M. Flash Continuous Glucose Monitoring Systems - Rapid HTA report for
diabetes subjects in insulin therapy Agenas: Rome, February 2018.
Contributions
Authors
Alessandra Lo Scalzo1, Iosief Abraha1, Matteo Andrea Bonomo2, Emilio Chiarolla1, Antonio
Migliore1, Simona Paone1, Sonia Toni3, Marina Cerbo1
1Agenas, Agenzia nazionale per i servizi sanitari regionali, Rome (Italy) 2ASST Grande Ospedale Metropolitano Niguarda-Regione Lombardia (Italy) 3Azienda Ospedaliera Universitaria Meyer -Regione Toscana (Italy)
Corresponding author
Alessandra Lo Scalzo ([email protected])
Clinical experts
Sonia Toni, [email protected] Responsabile della Diabetologia Pediatrica della Azienda Ospedaliero Universitaria Meyer di Firenze e Responsabile della struttura regionale di riferimento di Diabetologia Pediatrica (Regione Toscana) Matteo Andrea Bonomo, [email protected] Responsabile S.S.D. Diabetologia, ASST Grande Ospedale Metropolitano Niguarda - Piazza Ospedale Maggiore, 3 - 20162 Milano (Regione Lombardia)
External Reviewers
Claudio Maffeis – UOC Pediatria Indirizzo Diabetologico e Malattie del Metabolismo e Centro Regionale Diabetologia Pediatrica, Università e Azienda Ospedaliera Universitaria Integrata, Verona Silvia Ussai, PharmD, MD, MIHMEP, Regione Lombardia
Acknowledgements
The authors would like to thank Anna Maria Vincenza Amicosante, health statistician at Agenas, for her advice in consulting and analysing the national health related data set (e.g. Flusso Consumi and Flusso Contratti).
Declaration of conflict of interest and privacy
The Authors declare that they will not receive either benefits or harms from the publication of this document. None of the Authors has or has held shares, consultancies or personal relationships with any of the manufacturers of the devices assessed in this report.
Andrea Matteo Bonomo declares that in the last 3 years the congress expenses have been paid by Medtronic Italia and Novo Nordisk.
Sonia Toni declares that in the last 3 years she has worked for Sanofi Aventis and MERCK; she attended conferences organized by Abbott.
Claudio Maffeis declares to have participated in congresses sponsored by Abbott.
Silvia Ussai declares that in the last 3 years she has been a consultant for the Lombardy Region, Asl of Biella, Action Group A1/B3, AOU of Udine and participated in Mundipharma organized meetings.
Funding
The production of this HTA report was made possible by financial contributions from the Italian Ministry of Health and Agenas.
Index
Abstract .................................................................................................................................. 7
Sintesi in italiano ..................................................................................................................... 9
Introduction .......................................................................................................................... 16
1.Report’s objectives: policy and research questions ................................................................. 17
2.Health problem ................................................................................................................... 18
2.1 Method ........................................................................................................................... 18
2.2 Results ............................................................................................................................ 18
2.3 Discussion of results ......................................................................................................... 22
Bibliography .......................................................................................................................... 23
3. Description of technology and regulatory aspects ................................................................. 25
3.1 Methods .................................................................... Errore. Il segnalibro non è definito.
3.2 Results ...................................................................... Errore. Il segnalibro non è definito.
3.3 Discussion of results ................................................... Errore. Il segnalibro non è definito.
Bibliography .................................................................... Errore. Il segnalibro non è definito.
4. Current use of the technology ............................................................................................. 34
4.1 Method ........................................................................................................................... 34
4.2 Results ............................................................................................................................ 35
4.3 Discussion of Results ........................................................................................................ 41
5. Clinical effectiveness and safety .......................................................................................... 43
5.1 Methods .......................................................................................................................... 43
5.2 Results ............................................................................................................................ 44
5.3 Discussion of results ......................................................................................................... 54
Bibliography .......................................................................................................................... 58
6. Cost and economic evaluation ............................................................................................. 59
6.1 Methods .................................................................... Errore. Il segnalibro non è definito.
6.2 Results ...................................................................... Errore. Il segnalibro non è definito.
6.2.1 Analysis of literature ................................................ Errore. Il segnalibro non è definito.
6.2.2 Budget Impact Analysis ........................................... Errore. Il segnalibro non è definito.
6.3 Discussion of results ................................................... Errore. Il segnalibro non è definito.
Bibliography .................................................................... Errore. Il segnalibro non è definito.
7. Patients’ and social aspects ................................................................................................. 75
7.1 Method ...................................................................... Errore. Il segnalibro non è definito.
7.2 Results ...................................................................... Errore. Il segnalibro non è definito.
7.3 Discussion of results ......................................................................................................... 80
Bibliography .......................................................................................................................... 81
8. Conclusions ....................................................................................................................... 82
APPENDIX 1 - The Agenas adaptation of the EUnetHTA Core Model ® ....................................... 83
APPENDIX 2 – List of Assessment Elements ............................................................................. 85
APPENDIX 3 – Manufacturers involvement tools and procedure ................................................. 86
APPENDIX 4 -Questionnaire sent to Regions’ representatives from the National Network for HTA
(RIHTA – Rete Italiana per l’HTA)....................................................................................... 89
APPENDIX 5 – Extraction and analysis of regional decrees on FGM............................................. 91
APPENDIX 6 List of excluded studies with reasons .................................................................. 101
APPENDIX 7 – Analisi di impatto finanziario regionale del dispositivo FSL .................................. 103
APPENDIX 8 - List of patients associations responding to the public call and pointed out by experts
.................................................................................................................................... 118
APPENDIX 9 - Template to collect Patients Associations’views .................................................. 119
Glossary .............................................................................................................................. 126
7
Abstract
Diabetes mellitus is a metabolic disease characterized by hyperglycaemia secondary to an
insulin deficiency or a deficiency of its action. According to the World Health Organization in
Western countries about 90% of those affected by these disorders have type 2 diabetes
mellitus (T2DM) and 10% type 1 diabetes mellitus (T1DM). In insulin intensive patients,
insulin should be administered in adequate time, modality and dosage by multiple daily
injections (MDI) or subcutaneous insulin continuous infusion (CSII) and requires self-
monitoring of blood sugar levels. Home self-monitoring takes place with control of the
capillary blood glucose by means of reactive sticks (Self Monitoring of Blood Glucose -
SMBG). SMBG can be accompanied by domiciliary use of devices that are able to monitor
sugar in the interstitial fluid. Flash glucose monitoring systems (FGM) have recently been
introduced in Europe and represent a new approach. On the Italian market, only one FGM
was identified, the FreeStyle Libre (FSL) system, produced by Abbott Diabetes Care. FSL is a
Class IIb medical device for glucose measurement in interstitial fluids marketed in Europe
since September 2014. The CE mark was obtained in August 2014 and its indication of use
has recently been extended to pediatric patients (4-17 years) and pregnant women,
respectively in January 2017 and July 2017. The FSL is registered within the Medical Device
Database and Medical Devices Directory of the Italian Ministry of Health.
The present assessment report, after an introduction concerning the pathology and its
diffusion, presents a description of the technology and its regulatory status as well as a
comparative analysis of its diffusion in the Italian Regions based on regional decrees and
resolutions issued about FSL procurement. A systematic review of the literature has been
done with an evaluation of the available studies on efficacy and safety. We also performed a
structured collection of information provided by a series of patient associations about pros
and cons of different devices in daily management of diabetes and an evaluation of the
economic impact of FGM with simulation of various scenarios. From a clinical point of view
independent studies are necessary which compare FGM to SMBG but also to RTCGM (real
time continuous glucose monitoring) and that considers quality of life as an outcome. About
FSL’s spread, most of the Regions and PA have decided for its reimbursement with patients
eligibility criteria that are not always homogeneous. The price of the device and the
candidate population are the two main variables for determining the potential financial
impact of the FSL system. From the patient's point of view, the two non-capillary blood
8
glucose detection systems (i.e FGM and RTCGM) have both positive and negative aspects
and it is important to allow patients to make an informed choice that matches their
individual preferences and needs, with the help of the physician to optimize the daily
management of the disease.
9
Sintesi in italiano
Il diabete mellito è una malattia metabolica caratterizzata da iperglicemia secondaria ad un
deficit di insulina o a un deficit della sua azione. Secondo l’Organizzazione Mondiale della
Sanità nei paesi occidentali circa il 90% dei soggetti affetti da questi disturbi hanno il
diabete mellito di tipo 2 (DMT2) e il 10% il diabete mellito di tipo 1 (DMT1).
Il DMT1 è una malattia autoimmune che si sviluppa prevalentemente in età pediatrica ed è
causata da una distruzione, da parte del sistema immunitario, delle cellule beta pancreatiche
deputate alla produzione di insulina. Ciò determina una carenza assoluta o relativa della
secrezione di insulina. L'obiettivo della terapia sostitutiva è quello di mimare la funzione
beta cellulare e mantenere le concentrazioni ematiche di glucosio in un range fisiologico,
cercando di evitare o comunque limitare, sia episodi di ipoglicemia che di iperglicemia. Si
rende quindi necessario armonizzare continuamente la terapia insulinica, l’alimentazione e
l’esercizio fisico, tenendo anche conto dell’effetto iperglicemizzante dello stress, delle
malattie intercorrenti e, nel caso del bambino, anche nelle mutate condizioni in un corpo in
accrescimento. Il DMT2 si sviluppa più frequentemente in età adulta anche se si stanno
iniziando a registrare casi anche in età pediatrica, soprattutto nella fase puberale. Esso è
caratterizzato da insulino resistenza cui fa seguito una ridotta produzione di insulina da parte
delle cellule beta pancreatiche (glucotossicità). Nei soggetti con questa malattia l’approccio
terapeutico prevede una modifica dello stile di vita, l’utilizzo di antidiabetici orali cui
successivamente possono essere associati farmaci iniettivi e insulina.
Nei soggetti nei quali la produzione insulinica è totalmente assente o insufficiente, una
terapia insulinica intensiva prevede oggi la applicazione di schemi “basal-bolus”, allo scopo
di assicurare una insulinizzazione basale per tutte le 24 ore, alla quale si aggiunge una
componente “bolo” finalizzata ad ottenere concentrazioni più elevate di insulina nella fase
post-prandiale. Questo risultato può essere ottenuto con una terapia multiiniettiva (MDI –
Multiple Daily Injections), o con l’infusione sottocutanea continua di insulina mediante
microinfusore (CSII - Continuous Subcutaneous Insulin Infusion).
Nel caso della MDI, la componente basale è assicurata da insulina ad azione ritardata
(analoghi “long-acting”), iniettata solitamente in monosomministrazione, più frequentemente
la sera, mentre la componete “bolo” richiede la iniezione di insulina rapida (analoghi rapidi)
prima dei pasti principali.
10
Per la CSII viene invece utilizzata esclusivamente insulina rapida (analoghi rapidi), infusa in
continuo nelle 24 ore modulando la velocità secondo le necessità (infusione “basale”); si
aggiungono poi boli a comando al momento dei pasti e di eventuali snack, o per correggere
l’iperglicemia (“boli di correzione”).
Qualunque forma di terapia insulinica intensificata (MDI o CSII) richiede uno stretto auto-
monitoraggio dei livelli di glicemia, sia pre- sia post-prandiali L’automonitoraggio domiciliare
avviene con controllo della glicemia capillare mediante stick reattivi (Self Monitoring of Blood
Glucose - SMBG) che può essere affiancato dall’utilizzo domiciliare di dispositivi che sono in
grado di monitorare la glicemia nel liquido interstiziale.
Descrizione della tecnologia
Quando si parla di auto-monitoraggio della glicemia ci si riferisce alla misurazione dei livelli
glicemici effettuata direttamente dal paziente o dal suo care-giver. L’automonitoraggio della
glicemia capillare è eseguito su piccolissimi campioni di sangue capillare ottenuti tramite
puntura del polpastrello. Il campione viene raccolto su apposite strisce reattive che vengono
inserite in uno specifico dispositivo di lettura, il glucometro. Questo test viene effettuato per
ottimizzare il controllo glicemico. Conoscere il valore della glicemia rende possibile apportare
modifiche alla dose di insulina prima dei pasti, permette di verificare la correttezza della
dose di insulina effettuata, correggere con iniezioni supplementari l’iperglicemia riscontrata
in fase post-prandiale e situazioni di ipoglicemia. Vi sono poi sistemi di monitoraggio
continuo del glucosio (Continous Glucose Monitoring systems – CGM) che effettuano
misurazioni dei livelli glucosio nei fluidi interstiziali in modo semi-continuo, per mezzo di un
sensore glicemico impiantato nel tessuto sottocutaneo. In questo modo sono in grado di
identificare fluttuazioni che non sarebbero altrimenti identificate e di fornire notifiche o
allarmi legati ad eventi di iper o ipoglicemia. Le prime generazioni di CGM erano
retrospettive (holter type), ma successivamente sono stati sviluppati dei sistemi di
monitoraggio continuo della glicemia in tempo reale (RT-CGM) che consentono l’acquisizione
e la visualizzazione dei valori glicemici su un piccolo display. I sistemi RT-CGM sono diventati
commercialmente disponibili nel 2000 e richiedono una o più calibrazioni giornaliere che
vanno effettuate utilizzando valori di controllo ottenuti tramite auto-misurazioni sul sangue
capillare.
11
I sistemi flash per il monitoraggio del glucosio (FGM), oggetto del presente report, sono
stati recentemente introdotti in Europa e rappresentano un nuovo approccio. L’innovazione
principale è legata al modo di rilevare i valori di glucosio nel liquido interstiziale. Essi
vengono memorizzati nel sensore e resi accessibili mediante scansione, effettuata attraverso
un lettore o uno smartphone (quindi “on demand”, cioè forniti quando richiesti). I sistemi
FGM non richiedono la calibrazione giornaliera del sensore, tuttavia, non sono in grado di
interagire attivamente con il paziente poiché non inviano notifiche o avvisi in corrispondenza
di eventi di iper o ipoglicemia.
Aspetti regolatori
Sul mercato italiano è stato identificato un solo FGM, il sistema FreeStyle Libre (FSL)
prodotto da Abbott Diabetes Care. Il FSL è un dispositivo medico di Classe IIb per la
misurazione del glucosio nei fluidi interstiziali commercializzato in Europa da Settembre
2014. Il marchio CE è stato ottenuto ad Agosto 2014 e la sua indicazione d’uso è stata
recentemente estesa a pazienti pediatrici (4-17 anni) e donne in gravidanza, rispettivamente
a Gennaio e Luglio 2017. Il FSL è regolarmente registrato presso la Banca Dati e Repertorio
Dispositivi Medici del Ministero della Salute. Tale sistema è composto da un sensore ad ago,
pre-calibrato dal produttore, provvisto di un sistema di trasmissione interrogabile tramite
smartphone o apposito lettore portatile, il quale incorpora anche un glucometro per l’auto-
misurazione del glucosio su sangue capillare. Infatti, come indicato dal produttore, in talune
situazioni specifiche, i valori rilevati dal sensore ad ago vanno confermati attraverso misure
su sangue capillare. Il lettore FSL è dotato di un glucometro incorporato che potrebbe
costituire un vantaggio per il paziente in termini di comodità poiché evita l’utilizzo di un
ulteriore dispositivo. Il produttore propone il FSL come sostitutivo del SMBG e specifica che i
pazienti possono utilizzare i valori di lettura forniti dal sistema per prendere decisioni sui
dosaggi insulinici. Tuttavia, le indicazioni d’uso del dispositivo prevedono una serie di
eccezioni (momenti di rapida variazione glicemica, conferma di ipogliciemia o discordanza tra
sintomi e valori forniti dal sistema) in cui il valore fornito dal FSL deve necessariamente
essere verificato utilizzando una lettura da sangue capillare. Quest’ultima rimane dunque
non eliminabile del tutto.
12
Diffusione nelle Regioni italiane
Al fine di acquisire informazioni sulla diffusione di questa tecnologia, sulle caratteristiche dei
pazienti per i quali le Regioni e Province Autonome (PA) hanno ritenuto appropriata la
prescrizione e sulle modalità di acquisto e distribuzione, sono state consultate diverse fonti.
Alle Regioni e PA afferenti al Network italiano di HTA (RIHTA) è stato inviato un breve
questionario con richiesta di invio degli eventuali atti deliberativi con cui si è introdotto il
dispositivo. Ulteriori informazioni rispetto alla diffusione del FSL sono state fornite dal
produttore stesso e/o sono state ricercate sui siti web delle Regioni e PA.
Il FSL risulta introdotto in diverse Regioni e PA con modalità talvolta variabili in termini di
caratteristiche dei pazienti eleggibili, modalità di distribuzione e strategie di acquisto. La
maggior parte ha normato l’introduzione del FSL nel 2017, a seguito dell’emanazione del
DPCM del 12 gennaio 2017 (nuovi LEA) e dopo l’ottenimento del marchio CE da parte
dell’azienda (2014). Le Regioni che hanno introdotto in modo controllato il FSL prima del 2017
lo hanno fatto all’interno di studi finalizzati allo sviluppo di evidenze nel quadro di un trial (es.
Toscana, Emilia Romagna). I protocolli di studio individuati hanno evidenziato una variabilità
nella durata dello studio e nelle caratteristiche della popolazione (DMT1, DMT2 e popolazione
pediatrica). Altre regioni hanno modulato l’introduzione del FSL deliberando una sorta di
introduzione sperimentale, per un periodo di tempo limitato, solitamente di un anno, e con
richiesta, più o meno strutturata, di raccogliere una serie di dati finalizzati al monitoraggio
della efficacia e sicurezza del dispositivo. Alcune regioni hanno esplicitato e formalizzato gli
indicatori da misurare durante la fase sperimentale (per es. l’Umbria), mentre altre hanno
introdotto il FSL per un tempo limitato, ma non hanno formalizzato indicatori e tempi di
raccolta (Marche, Basilicata). Relativamente alle caratteristiche dei pazienti con DMT2 si è
registrata una qualche diversità nella definizione dei criteri e, nel caso di identificazioni di
criteri sovrapponibili, nella diversità della loro valorizzazione. Ad esempio il valore dell’HbA1c
varia da 8 a 10% (corrispondente a 64-86 mmol/mol), il numero dei controlli della glicemia da
3 a 10 ed il numero di iniezioni giornaliere da 3 a 6. La strategia di acquisizione tramite
centrale unica non è presente in tutte le regioni e la distribuzione del FSL avviene con
modalità differenti.
13
Efficacia e Sicurezza
Al fine di valutare le evidenze relative all’uso del FSL rispetto alle altre modalità di
monitoraggio è stata lanciata una strategia di ricerca nei seguenti database: Pubmed,
Cochrane Library ed EMBASE. Dopo opportuna valutazione dei titoli ed abstract, e degli
articoli integrali potenzialmente eleggibili, sono stati individuati 2 studi che hanno soddisfatto i
criteri di inclusione. I due articoli presentano studi clinici randomizzati multicentrici in cui sono
stati arruolati 491 partecipanti in diversi Paesi Occidentali. In uno studio i soggetti inclusi
erano affetti da DMT1 con età media di 43 anni, mentre nel secondo studio i soggetti erano
effetti da DMT2 con età media di 64 anni. Gli studi avevano come outcome primario la
riduzione del tempo trascorso in ipoglicemia [Bolinder 2016] e la differenza di emoglobina
glicosilata tra i due gruppi di intervento e come comparatore il SMBG. Dal punto di vista
metodologico, entrambi gli studi sono risultati a rischio di bias di selezione, con una limitata
perdita al follow-up. Entrambi gli studi erano a rischio di detection bias in quanto il valutatore
dell’outcome probabilmente non operava in condizioni di mascheramento. Tuttavia, il mancato
mascheramento non poteva inficiare la qualità degli studi relativamente agli outcome
considerati oggettivi come l’Hb1Ac e gli eventi ipoglicemici; mentre la qualità di vita non
poteva essere immune dal detection bias.
Dalla valutazione quantitativa degli studi è emerso che per gli outcome clinici di interesse del
presente report, ovvero la differenza in termini di Hb glicata, e di eventi avversi legati alla
ipoglicemia non si sono osservate differenze rilevanti. Analogamente non si sono osservate
differenze in termini di eventi avversi generali. Va segnalata invece una differenza significativa
a favore del FGM per quanto riguarda il tempo trascorso in ipoglicemia e gli eventi
ipoglicemici rilevati dal sensore, e alcuni parametri della qualità di vita. Abbiamo approfondito,
tramite coinvolgimento delle associazioni pazienti disponibili, il contenuto di questo valore
aggiunto in termini di qualità della vita.
Il punto di vista delle associazioni pazienti
Abbiamo pubblicato una richiesta di collaborazione sul sito Agenas affinché le associazioni dei
pazienti diabetici (AP) interessate esplicitassero la loro disponibilità a essere coinvolte per la
raccolta di informazioni su aspetti relativi alle tecnologie in analisi. Dodici associazioni hanno
14
dato la loro disponibilità e tre di esse, aggreganti diverse altre associazioni di livello nazionale
o provinciale, hanno dato un feedback effettivo riempiendo il questionario inviato da Agenas.
Le AP hanno evidenziato aspetti positivi e negativi nell’utilizzo del FSL, del RT-CGM, nonché
della misurazione su sangue capillare. I lettori real time che hanno la funzione di allarme
come avviso per le ipoglicemie, presentano in ciò un valore aggiunto sottolineato da più
associazioni. Comodità e vestibilità, nonché la possibilità di non calibrare, sono alcune delle
caratteristiche apprezzate del FSL. Questo tipo di lettore è ritenuto utile dalle AP per alcune
categorie di pazienti, quali persone che fanno professioni particolari, come atleti o musicisti,
per i quali il numero di controlli capillari crea disagio per un uso maggiore delle
mani/polpastrelli. Dall’analisi delle risposte emerge che a parità di efficacia e sicurezza, è
importante per i pazienti poter accedere a nuove tecnologie, lasciando loro la possibilità di
scegliere con il medico la migliore terapia date anche le diverse preferenze individuali.
Aspetti economici
Per quanto riguarda l’analisi degli aspetti economici ad oggi non sono disponibili in letteratura
studi di costo o di costo efficacia sull’utilizzo del FSL. Sono stati tuttavia analizzati due articoli
di letteratura grigia, forniti e finanziati dal produttore della tecnologia, che hanno messo in
comparazione il sistema FSL con il SMBG concludendo la costo efficacia del dispositivo per
pazienti affetti da DMT1 e DMT2. E’ stata quindi svolta una analisi di impatto finanziario
attraverso la costruzione di un modello per la stima della spesa per i dispositivi nel biennio
2018-2020. Tale modello ha tenuto conto dell’impatto finanziario del solo FSL e ha utilizzato
sia le informazioni fornite dal produttore, sia quelle rilevate nel Flusso Contratti del Ministero
della Salute. Utilizzando tali fonti si è rilevato che nelle Regioni e PA che hanno imputato le
informazioni nel flusso contratti, il costo del lettore è nullo e l’acquisto riguarda solo i sensori.
Inoltre, in base alle informazioni del produttore, sono fornite gratuitamente un numero di
strisce sufficienti a coprire il fabbisogno di misurazione della glicemia su sangue capillare. Il
prezzo dei sensori è risultato variabile da regione a regione. Effettuando una stima della
popolazione diabetica di riferimento nelle varie realtà regionali, abbiamo costruito un modello
con singole stime per ogni Regione e PA, relative alle risorse finanziarie necessarie per
l’acquisto dei sistemi FSL nel periodo 2018-2020 disponibili in appendice al presente report.
15
Conclusioni
In sintesi, l'uso del FCGM ha determinato una riduzione di HbA1c e tassi di eventi avversi
ipoglicemici simili a quelli osservati durante l’uso di SBGM, peraltro con una diminuzione del
tempo trascorso in ipoglicemia, ed un miglioramento della qualità di vita. La tecnologia flash
sensing del glucosio è sicura e, salvo che in situazioni specifiche nella quali si ritenga
necessaria una precisa determinazione del dosaggio insulinico finalizzata ad una effettiva
ottimizzazione del controllo glicemico, può essere utilizzata senza rischi significativi al posto
dell'auto-monitoraggio standard della glicemia per la gestione glicemica di soggetti diabetici
trattati con terapia insulinica. Sono tuttavia necessari ulteriori studi per valutare l'efficacia di
questa tecnologia in pazienti con diabete meno ben controllato, in gruppi di età più giovane e
donne in stato di gravidanza. Inoltre, per supportare decisioni di tipo clinico, sono necessari
studi indipendenti, che considerino anche outcome come la qualità della vita nell’uso del
dispositivo e che valutino il FGM rispetto agli altri sistemi RT-CGM in commercio. Il disegno di
studio auspicabile potrebbe essere quello che permette la comparazione dei tre metodi
(SMBG, RTCGM e FGM). Il SMBG infatti rappresenta una modalità di controllo indispensabile
per il diabetico in terapia insulinica, dato che in molte occasioni è necessario un controllo
capillare prima di assumere una decisione terapeutica. Queste considerazioni potrebbero
essere riviste in futuro, alla luce di eventuali nuovi studi non ancora pubblicati durante la
stesura del presente documento. Ad oggi si è rilevato che il FSL è diffuso nel territorio italiano
e già la maggior parte delle Regioni e PA lo hanno acquistato, spesso con percorsi controllati
e con modalità e criteri di eleggibilità non sempre del tutto omogenei. Inoltre, il prezzo del
dispositivo e la popolazione candidabile rappresentano le due principali variabili per la
determinazione del potenziale impatto finanziario. Dal punto di vista del paziente i due sistemi
di rilevazione della glicemia non capillare (FGM e RTCGM) sembrano avere aspetti sia positivi
che negativi, da ciò emerge l’importanza di poter effettuare una scelta condivisa con il proprio
medico della modalità di controllo glicemico che sia la più adatta alle specifiche condizioni di
vita del paziente, anche al fine di ridurre il carico nella gestione della malattia.
16
Introduction
The present rapid HTA report was carried out following the Agenas’ Manual of Procedures
[Agenas, 2014] and the procedures outlined in the Agency's Corruption Prevention and
Transparency Plan (2017-2019) [Agenas, 2017]. This document was developed following the
EUnetHTA Core Model® application for “Medical and surgical procedures” version 2.0. The
Core Model is divided into domains representing each a specific area of technology impact to
be assessed. Each domain contains a series of research questions or Assessment Elements
(AEs) identified by a capital letter and number (e.g A0001). To test the Core Model
applicability, an adapted model was elaborated by Agenas (see Appendix 1 for a full
description). The use of the Core Model is mirrored in the structure of this report, where each
chapter corresponds to a domain and reports the AEs considered for the assessment.
This Rapid Assessment relies on the procedures and methods presented in the Agenas HTA
Manual and the Eunehta Core Model. The evaluation will be thus carried on by Domains and
for each of them a set of AEs form the Agenas version of the Core Model will be selected. In
each chapter’s methods paragraph a list of the selected AEs is provided together with the
methodology to answer them. We will focus on a reduced set of domains: technology,
regulation, current use, effectiveness and safety, economic and patient and social aspects.
17
1. Report’s objectives: policy and research questions
The present report will focus on the assessment of the Flash Glucose Monitoring Systems
(FGM) and its comparators in people with Type 1 Diabetes Mellitus (T1DM) and Type 2
Diabetes Mellitus (T2DM). We will provide an assessment on the FGM versus comparators
presenting regulatory status of the device, technical characteristics of the technology and its
comparators, an analysis of its spread within national context and an assessment of its
effectiveness, safety and costs.
Policy question
What is the advantage of introducing the FGM in subjects that are under insulin therapy in
terms of clinical outcomes, patient perspectives and costs for INHS?
Research questions
What is this technology and the comparator(s)?
Which specific characteristics does have the device under assessment and how does
it works?
Who manufactures the technology?
In what context and level of care are technology and the comparator(s) provided?
What equipment and supplies are needed to use the technology and the
comparator(s)?
For which indications has the technology received marketing authorisation or CE
marking?
What is the effectiveness and safety of the technology?
Which is the technology’s and comparators’ costs per person/year and their
reimbursement status? Which is the technology diffusion across Italian Regions and
Autonomous Provinces (Regions and PAs) and which are the criteria to appropriately
deliver it?
How do patients perceive the technology under assessment? Which are the pros and
cons of its use from patients/caregivers point of view? Are there specific group of
patients that would benefit or experience barriers?
18
For each investigated domain, the selected Assessment Elements are listed in Appendix 2.
2. Health problem
2.1 Method
We selected the following Assessment Elements:
Health problem was reported in a descriptive summary defined by international and national
literature review: in particular, we searched for review articles, epidemiological studies and
disease registers. Informal interviews with experts were also carried out to clarify the current
management of disease in Italy.
2.2 Results
Target population
Diabetes mellitus (DM) is a chronic disease of the metabolism characterized by poorly
regulated blood glucose levels, which may arise from defects in insulin secretion or insulin
resistance. DM is a common and serious health problem worldwide. In Western countries
around 90% of subjects affected with DM are estimated to have type 2 Diabetes Mellitus
(T2DM) [WHO 2016]. T2DM typically develops in adult people above the age of 40 although
younger onset is becoming more common and it is generally characterized by insulin
resistance. Conversely, Type 1 Diabetes Mellitus (T1DM) is caused by a cellular-mediated
autoimmune destruction of pancreatic beta cells resulting in deficiency in insulin secretion. In
Assessment Element ID Research question
A0001 A0001a:For which health condition is the technology proposed? A0001b: Which group of patients represents the target population for the technology?
A0001c: For what purposes is the technology used?
A0006 What are the statistics of incidence, prevalence, morbidity, and mortality of the health condition?
19
Italy, population based studies report that the overall diabetes prevalence ranged between
3.4%, estimated in 2004 [Brocco 2007] to 4.1% estimated in 2007 [Monesi 2012], whereas
the incidence remained stable at a rate of 0.5%. More recent data provided by ISTAT (Italian
Institute of Statistics) show that the age standardised prevalence rates range from 4.1% in
2000 to 4.9% in 2016. All the above studies however did not differentiate T1DM from T2DM
in their estimates.
Both deficit in insulin secretion and insulin resistance lead to chronic hyperglycaemia.
Treatment for T2DM may include lifestyle modification, weight reduction or oral
hypoglycaemic agents that may delay the use of life-long insulin replacement to control blood
glucose. To date there is no cure for T1DM and treatment consists in life-long insulin
replacement to control blood sugar levels, starting right since the onset. Long-term
complications of DM include macrovascular diseases such as cardiovascular death, myocardial
infarction, stroke and peripheral ischemia as well as microvascular complications such as
retinopathy, nephropathy and neuropathy (A0001a) [DCCT 1993; Almdal 2004]
The primary goal for subjects affected with diabetes is to obtain normal glucose
concentrations without causing hypoglycaemia. To achieve this goal, T1DM and T2DM
subjects that are under insulin therapy will need to adjust timing and dosing of insulin in
home care setting and via self-monitoring systems. Generally, T1DM subjects use self-
monitoring of capillary blood glucose (SMBG) to optimise glycaemic control based on daily
insulin injections and adjust insulin administration based on pre-prandial and post-prandial
self-monitored blood glucose [DCCT 1993].
Insulin therapy can be intensive from the diagnosis (basal/bolus or CSII, plus SMBG/CGM,
plus education) in order to obtain a tight management of blood sugar levels, and decrease the
risk of both acute and long term diabetic complications. This regime consists of frequent
testing of glucose levels and either regular shots of insulin (multiple daily injections - MDI) or
use of an insulin pump (A0001b). The intensive insulin therapy guarantees the basal
component and the ones that are needed to limit any post prandial glycaemic (basal-blolus
insulin therapy). If the patient uses MDI the basal component is given by one or more
injections of long-acting insulin, while the bolus component is given by the injection of rapid
insulin before each meal and, if necessary, after each snack. There is also a third component,
20
for correction, that aims to correct via more insulin doses or extra injections any probable
hyperglycaemia. For patients using CSII the basal component is given by the continuous
infusion that can be modulated during the whole day (H24), while the bolus component is
given by the insulin bolus for each meal. There is a correction component also here. If one
uses CSII can be used only rapid insulin or rapid analogous [DCCT, 1993].
Frequency of blood glycemic control varies according to the type of patient and therapy.
Children need 4 or more daily injections or CSII, seven or more glycaemic tests or CGM
[Danne T et al, 2014; Rewers MJ et al, 2014; Scaramuzza A et al 2014; SIEDP, 2015]. For
T1DM subjects in intensive insulin therapy both the Italian Standard of care (2016) and the
American Diabetes Association (2018), agree on the necessity of a glycaemic control before
each main meal and before any snack (as this is essential to decide the quantity of insulin on
the basis of the carbohydrates’ calculation) occasionally after main meals and snacks, before
going to bed and before any physical exercises and always if there is a suspected
hypoglycaemia and after correcting them (an average of 150-200 glycaemic strips per
months) [DCCT, 2008, AMD-SID 2016, ADA, 2018]
For testing of glucose levels, continuous glucose monitoring systems (CGMs) measure
interstitial fluid glucose levels to provide semi-continuous information about glucose levels.
They may identify fluctuations that would not be identified with SMBG alone and may have
alarm functions that can be set to personalised thresholds of hyper or hypoglycaemia
(A0001c). First generations of CGMs were retrospective: they were able to measure the
glucose concentration during a certain time span, store the values, and allow their following
download. Real-time continuous glucose monitoring systems (RT-CGM) were developed after
that, by adding features that allow the actual continuous provision of glucose concentration
values on a display [Langendam 2012].
Burden of disease
An Italian healthcare monitoring system based on administrative data (ARNO Observatory),
identified a population-based multiregional cohort of subjects aged 0–29 years with T1DM
between the period 2002–2012. Type 1 diabetes was defined by at least two prescriptions of
insulin over 12 months and continuous insulin-treatment in the subsequent years. Overall
21
2357 incident cases of type 1 diabetes aged 0–29 years were identified. Incidence rates were
15.8/100,000 (95% CI 14.9 to 16.8) in ages 0–14 years and 16.3/100,000 (15.4 to 17.2) in
ages 15–29. Prevalence estimates were 137/100,000 and 166.9/100,000 for the two age
groups [Bruno 2016].
Another retrospective population-based study conducted through the individual-level linkage
of several health administrative databases of the Friuli Venezia Giulia calculated the incidence
and prevalence of the population 0-18 years of age. The incidence rate of T1DM between the
period 2010-2013 was 15.8 new cases/100,000 person-years. The prevalence, estimated for
the year 2013, was 150.1/100,000 inhabitants [Valent 2016].
The RIDI study [Bruno 2010] investigated the temporal trend of type 1 diabetes in children
age 0-14 years in Italian registries. The incidence rate resulted 12.26 per 100,000 person-
years and significantly higher in boys (13.13 - 95% CI 12.66-13.62) than in girls (11.35 -
10.90-11.82). At a regional level, a retrospective population-based study conducted in
Lombardy region, evaluated the incidence, prevalence and mortality of combined population
with T1DM and T2DM subjects. The study reported a rise in the prevalence from 3.0% in 2000
to 4.2% in 2007 whereas the incidence remained constant during the study period with a rate
of 4/1000 per year. The study reported also a rate of mortality of 43.2/1000 in 2001 and
40.3/1000 in 2007 with a 6.7% decrease [Monesi 2012].
Similarly, in the Veneto region, retrospective evaluation of administrative databases showed
that incidence of paediatric T1DM was 165/100,000 person-years whereas prevalence was 126
cases/100,000 inhabitants [Marigliano 2015].
A study conducted on resident population of the province of Turin, Italy, aged 30–49 years in
the period between 1999 to 2001 identified diabetic subjects through diabetes Clinics (primary
source), and the centralized file of all patients who have obtained exemption from payment
for drugs, syringes, and glucose-monitoring strips owing to a diagnosis of diabetes (secondary
source). The study found an incidence of T1DM of 7.3 per 100,000 person-years (6.2–8.6) and
an incidence of T2DM of 68.7 (63.7–74.1) [Bruno 2005]. In Bruneck, a small town of 13,500
people, located in northeastern Italy, a study involved individuals who were aged 40–79 years
to undergo oral glucose tolerance test, assessment of physiological risk factors for diabetes,
22
including insulin resistance (homeostasis model assessment, HOMA-IR), and post challenge
insulin response (Sluiter’s Index). After 5 year follow-up, 64 individuals had developed
diabetes, corresponding to a population-standardized incidence rate of 7.6 per 1,000 person-
years (A0006) [Bonora 2004].
2.3 Discussion of results
Several studies were conducted to assess the epidemiology of diabetic subjects in Italy. There
were some variations in the incidence and prevalence and incidence of both T1DM and T2DM.
T1DM incidence ranged between 7 to 16 cases per 100,000 residents whereas T1DM
prevalence ranged between 126 and 167 per 100,000 residents. No clear morbidity and
mortality data were retrieved. Prevalence for T2DM subjects remained around 4-5%. Data on
mortality were limited but one study reported a decrease in the rate of mortality.
23
2.4 Bibliography
AMD-SID. Standard Italiani Per La Cura Del Diabete Mellito 2016. Controllo glicemico . Automonitoraggio della glicemia. In: p 45-56. www.standarditaliani.it (last accessed, February, 2017). American Diabetes Association, Assessment of glycemic control In: Standards of Medical Care in Diabetes 2018. Diabetes Care 2018 41 (Suppl.1):S55-S64. Almdal, T.H. ScharlingJ. S. Jensen (2004). "The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up." Arch Intern Med 164(13): 1422-6. Bonora, E.S. KiechlJ. Willeit (2004). "Population-based incidence rates and risk factors for type 2 diabetes in white individuals: the Bruneck study." Diabetes 53(7): 1782-9. Brocco, S.C. VisentinU. Fedeli (2007). "Monitoring the occurrence of diabetes mellitus and its major complications: the combined use of different administrative databases." Cardiovasc Diabetol 6: 5. Bruno, G.M. MauleF. Merletti (2010). "Age-period-cohort analysis of 1990-2003 incidence time trends of childhood diabetes in Italy: the RIDI study." Diabetes 59(9): 2281-7. Bruno, G.E. PaganoE. Rossi (2016). "Incidence, prevalence, costs and quality of care of type 1 diabetes in Italy, age 0–29 years: The population-based CINECA-SID ARNO Observatory, 2002–2012." Nutrition, Metabolism and Cardiovascular Diseases 26(12): 1104-1111. Bruno, G.C. Runzo P. Cavallo-Perin (2005). "Incidence of type 1 and type 2 diabetes in adults aged 30-49 years: the population-based registry in the province of Turin, Italy." Diabetes Care 28(11): 2613-9. Danne T et al Insulin treatment in children and adolescents with diabetes. Pediatric diabetes 2014; 15: 115-134 DCCT (1993). "The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group." N Engl J Med 329(14): 977-86. ISTAT, Anni 2000-2016 Il Diabete in Italia, 20 luglio 2017 https://www.istat.it/it/files//2017/07/REPORT_DIABETE.pdf last accessed December 2018. Marigliano, M.E. TadiottoA. Morandi (2015). "Epidemiology of type 1 diabetes mellitus in the pediatric population in Veneto Region, Italy." Diabetes Research and Clinical Practice 107(3): e 19-e21. Monesi, L.M. BavieraI. Marzona (2012). "Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study." Diabet Med 29(3): 385-92.
24
Rewers MJ.et Al. assessment and monitoring of glycemic control treatment in children and adolescents with diabetes. Pediatric Diabetes 2014; 15: 102-114 Scaramuzza A et Al. Recommendations for self monitoring in pediatric diabetes: a consensus statement by ISPED. Acta Diabetol 2014; 51: 173-184 SIEDP. Raccomandazioni sulla terapia insulinica in età pediatrica. Acta Biomedica 2015; 86 Valent, F.R. CandidoE. Faleschini (2016). "The incidence rate and prevalence of pediatric type 1 diabetes mellitus (age 0-18) in the Italian region Friuli Venezia Giulia: population-based estimates through the analysis of health administrative databases." Acta Diabetol 53(4): 629-35. WHO (2016). "World Health Organization. Diabetes. www.who.int/mediacentre/factsheets/fs312/en/" (accessed 15 March 2017).
25
3.Description of technology and regulatory aspects
3.1 Methods
The Assessment Elements of those domains were:
Assessment Element ID (TEC) Research question
B0001b What is(are) the comparator(s)?
B0005b In what context and level of care is(are) the comparator(s) used?
B0001 What is this technology?
B0003 What is the phase of development of the technology?
B0004 How is the technology used?
B0005 In which setting and level of care is the technology used?
B0007 Does the technology require additional/special equipment/tools or
accommodation?
B0009 What disposables and supplies are needed to use the technology?
F0001 F0001a: Is the technology new/innovative?
F0001b: Is the technology an add-on, a replacement or a modification of
the standard mode of care?
Assessment Element ID (REG) Research question
A0020 What is the marketing authorization status of the technology?
The technology, its technical characteristics, and regulatory status (CE marking and FDA
approvals) are presented together with a description of its comparators. To describe the
device under assessment we integrated information gathered by a structured questionnaire
sent to the manufacturer (see Appendix 3) with ad hoc internet searches on manufacturers’
press release websites, brochures, instructions for use (IFU) documents, and regulatory
bodies’ databases. To describe the comparators we used the latest scientific literature
(secondary studies like literature reviews and HTA reports).
26
3.2 Results
Technologies description
Self-monitoring of blood glucose (SMBG) refers to home blood glucose testing for people with
diabetes. SMBG is performed using capillary blood glucose to optimise glycaemic control
based on daily insulin injections and adjust insulin administration based on pre and post
prandial values. One of the finger tips is punctured with a lancet to allow capillary blood to
get in contact with a testing strip, which is specific for the reader (glucometer). Continuous
glucose monitoring systems (CGMs) are alternative to SMBG and measure interstitial fluid
glucose levels to provide semi-continuous information about glucose levels. They may identify
fluctuations that would not be identified with SMBG alone and may have alarm functions that
can be set to personalised thresholds of hyper or hypoglycaemia. First generations of CGMs
were retrospective: they were able to measure the glucose concentration during a certain
time span, store the values, and allow their download at a given time. Real-time continuous
glucose monitoring systems (RT-CGM) were developed after that, by adding features that
allow the actual continuous provision of glucose concentration values on a display. RT-CGM
first became commercially available in the year 2000 [Rodbard 2016]. RT-CGM can provide
glucose measurements as often as every 5 minutes and can be considered a potential
alternative to SMBG (in particular, those systems with proven high accuracy in glycaemia
estimation). Most RT-CGM use a needle-type glucose sensor implanted in the subcutaneous
tissue to monitor the glucose concentration of interstitial fluid in diabetic subjects. RT-CGM
are typically able to show glucose values and paths in real time and to perform monitoring
functions within the 24 hours (notifying high or low glucose levels with alarms that can also
be predictive). These systems require daily calibration using control values obtained from
capillary blood measurements. Calibration should be performed at times of glycaemic stability,
avoiding moments of rapid glycaemic fluctuations (B0001b, B0005b).
Flash glucose monitoring systems (FGM) have recently been introduced in Europe [Rodbard
2016] and represent a new approach for continuous glucose monitoring. The system consists
of two main components: a glucose sensor implanted in the subcutaneous tissue to monitor
the glucose concentration in the interstitial fluid embedding a transmitter with Near Field
Communication (NFC) technology and a dedicated hand-held reader or an app-based reader.
27
The main innovation is related to the way of detection of the glucose values: patient’s glucose
levels are stored for up to 8 hours, in the sensor, which in turn, is accessed by scanning the
reader over the sensor (i.e. system on demand). FGM do not require daily calibration of the
sensor but not actively interact with the patients since it is not able to send notifications
(alerts) in cases of high/low glucose levels [Perestelo-Pérez 2016] (B0001).
Only one FGM has been identified on the Italian market, the FreeStyle Libre system
manufactured by Abbott Diabetes Care (Table 1) which is currently in post-marketing phase
and is the only version marketed in Europe since its launch in 2014 (B0003).
Table 3.1: Flash continuous glucose monitoring systems (FGM) identified and available on the Italian market
Manufacturer Device name BD/RDM
registration number(s)
Package kit
Abbott Diabetes Care Ltd
FreeStyle Libre Sensor 1205274
• Sensor pack • Sensor applicator • Alcohol wipe • Product insert
FreeStyle Libre Reader 1205272
• Reader • USB cable • Power adapter • User’s manual • Quick start guide
FreeStyle Libre Software 1205277 Software for PC or Mac.
AirStrip Technologies, Inc. LibreLink* 1338314 1480279 1614139
App for smartphone (Android).
*During the public consultation of the report the manufacturer stated that since March 2018 this App has been disposed and replaced by the App “FreeStyle LibreLink” produced by Abbott and available for use on Android phones running Android 5.0 and higher with NFC functionality and iPhone 7 and later running iOS 11 and later. The app is distributed through Google Play and the Apple App Store and is free.
Source: Data from BD/RDM database (accessed on 07th November 2017) and manufacturer.
Note: All the devices listed in the table are CE marked and registered within the Italian National Medical Devices Inventory and Database (Banca Dati e Repertorio Dispositivi Medici – BD/RDM).
The FreeStyle Libre system is a sensor-based, factory-calibrated FGM that measures glucose
levels in the interstitial fluid. It works using flash technology, i.e., data such as glucose levels,
trends, and variability is automatically stored in the sensor and can be accessed by a 1-
second scan of the sensor using a specific reader able to collect and present results on a
screen. The system has two main components: a disposable sensor and a reader; a dedicated
software is available as optional (Table 3.1).
28
The sensor unit, which embeds a transmitter, has a sterile filament (0.4 mm wide,
inserted approximately 5 mm under the skin) attached to a small disc
(30 mm × 5 mm), which is applied to the back of the upper arm using a dedicated
applicator device (provided as a part of the sensor kit). The sensor measures glucose
in interstitial fluid for up to 14 days without additional calibration, updates readings
every minute, and stores data every 15 minutes. The sensor maintains and can
transfer to the reader 8 hours of data with each scan.
The reader holds up to 90 days of data, which can be downloaded to a computer for
a more extensive analysis of the glycaemic data. The reader displays trends and
alerts but does not have real-time alarms for the patient. The reader is provided with
a built-in glucose meter that can be used to test blood glucose and blood ketone or
to test the meter and strips with control solution.
The dedicated software is capable of generating an ambulatory glucose profile (AGP)
report that conforms to the published standard. The software can also be used to
generate a chart to highlight areas that individuals and clinicians should investigate
further. In particular, three digital products are available through Google Play and
the Apple App Store for free: two mobile medical apps (FreeStyle LibreLink and
LibreLinkUp), and a cloud-based diabetes management system (LibreView by Newyu,
Inc.).
The smartphone app allows the patients to read values directly on a smartphone
provided with an NFC receiver and running Android or iOS (information provided by
the manufacturer) (B0004).
The FreeStyle Libre system is intended for self-measurement of glucose levels and is
designed for home-care setting (B0005). It does not require additional or special equipment
or accommodation for its use (B0007) but for using the built-in glucometer, specific test
strips provided by the manufacturer are necessary (Table 3.2) (B0009).
29
Table 3.2: Disposables and supplies needed for the FreeStyle Libre system
Manufacturer Device name BD/RDM registration number(s)
Abbott Diabetes Care Ltd FreeStyle Optium blood glucose test strips 1241556, 1241583
Abbott Diabetes Care Ltd FreeStyle Optium ketone test strips 1241726
Source: Data from BD/RDM database (accessed on 13th September 2017) and manufacturer.
Note: all Disposable and supplies are registered within the Italian National Medical Devices Inventory and Database (Banca Dati e Repertorio Dispositivi Medici – BD/RDM).
The FreeStyle Libre system is the first FGM on the market. According to the manufacturer
(see indication from IFU document at Table 3.4), it is designed to replace blood glucose
testing in the self-management of diabetes with some exceptions in which a blood
glucometer is recommended to check the current glucose readings from the FreeStyle Libre
system (F0001):
During times of rapidly changing glucose levels (i.e., when glucose levels are falling
rapidly, glucose readings from the sensor may be higher than actual levels while,
when glucose levels are rising rapidly, glucose readings from the sensor may be
lower than actual levels).
In order to confirm hypoglycaemia or impending hypoglycaemia as reported by the
sensor;
If symptoms do not match the system reading.
Regulatory status
The FreeStyle Libre system is a Risk Class IIb medical device marketed in Europe since
September 2014. The CE mark was obtained in August 2014 and its indication for use has
been recently expanded to paediatric patients (4-17 years old) and pregnant women in
January 2017 and July 2017, respectively (Table 3.3). Indications for use as per IFU have
been reported in Table 3.4 together with contraindications, warnings and cautions (A0020).
Like all medical devices, FreeStyle Libre system requires registration to the Italian National
Medical Devices Inventory and Database (Banca Dati e Repertorio Dispositivi Medici –
BD/RDM) to be purchased by public hospitals.
30
Table 3.3: Approval details of FreeStyle Libre system
Manufacturer Device name CE mark FDA approvals
Abbott Diabetes Care Ltd FreeStyle Libre Flash Glucose Monitoring System Aug 2014 Jan 2017* Jul 2017**
Sep 2017
* Expanded indication to paediatric patients (4-17 years old).
** Expanded indication to and pregnant women.
Source: Data from manufacturer.
31
Table 3.4: Indications for use, contraindications, warnings and cautions for the FreeStyle Libre system
Indications Contraindications Warnings Cautions
The FreeStyle Libre Flash Glucose Monitoring System is
indicated for measuring interstitial fluid glucose levels in people (age 4 years and older) with diabetes mellitus,
including pregnant women. The indication for children (aged 4–17) is limited to those who are supervised by a caregiver who is at least
18 years of age. The caregiver is responsible for managing or assisting the child to manage the FreeStyle
Libre Flash Glucose Monitoring System and also for interpreting or assisting the child to interpret FreeStyle
Libre readings. It is designed to replace blood glucose testing in the self-management of diabetes with the exceptions listed
below. Under those circumstances, use a blood glucose meter to check the current glucose readings from the
FreeStyle Libre Flash Glucose Monitoring System sensor. During times of rapidly changing glucose levels,
interstitial glucose levels as measured by the sensor
and reported as current may not accurately reflect blood glucose levels. When glucose levels are falling
rapidly, glucose readings from the sensor may be higher than blood glucose levels. Conversely, when glucose levels are rising rapidly, glucose readings
from the sensor may be lower than blood glucose levels.
In order to confirm hypoglycaemia or impending hypoglycaemia as reported by the sensor.
If symptoms do not match the FreeStyle Libre Flash Glucose Monitoring System reading. Do not ignore symptoms that may be because of low blood glucose
or high blood glucose.
The FreeStyle Libre Flash Glucose Monitoring
System must be removed prior to Magnetic Resonance Imaging (MRI).
The FreeStyle Libre Flash Glucose Monitoring System
contains small parts that may be dangerous if swallowed.
During times of rapidly changing glucose (more than 0.1 mmol/L per minute), interstitial fluid glucose
levels as measured by the FreeStyle Libre Flash Glucose Monitoring System Sensor may not accurately
reflect blood glucose levels. Under these circumstances, check the Sensor glucose readings by
conducting a fingerstick test using a blood glucose meter.
In order to confirm hypoglycaemia or impending hypoglycemia as reported by the FreeStyle Libre Flash
Glucose Monitoring System Sensor, conduct a fingerstick test using a blood glucose meter.
Do not ignore symptoms that may be due to low or high blood glucose. If you have symptoms that do not
match the FreeStyle Libre Flash Glucose Monitoring System reading or suspect that your reading may be inaccurate, check the reading by conducting a
fingerstick test using a blood glucose meter. If you are experiencing symptoms that are not consistent
with your glucose readings, consult your health care professional.
On rare occasions, you may get inaccurate Sensor
glucose readings. If you believe your glucose readings are not correct or are inconsistent with
how you feel, perform a blood glucose test on your finger to confirm your glucose. If the problem continues, remove the current Sensor
and apply a new one.
Performance of the System when used with other implanted medical devices, such as pacemakers,
has not been evaluated.
The Reader is for use by a single person. It must
not be used on more than one person including other family members due to the risk of spreading
infection. All parts of the Reader are considered biohazardous and can potentially transmit infectious diseases, even after performing the
cleaning procedure.
Some individuals may be sensitive to the adhesive that keeps the Sensor attached to the skin. If you notice significant skin irritation around or under
your Sensor, remove the Sensor and stop using the FreeStyle Libre system. Contact your health
care professional before continuing to use the FreeStyle Libre system.
Source: Data from manufacturer (as reported within IFU document for the European market).
32
3.3 Discussion of results
Compared to RT-CGM, FGM represents a different approach for continuous glucose monitoring
allowing storage of patient’s glucose levels up to 8 hours within the sensor and data visualisation
by a hand-held reader which is scanned over the sensor. Only one FGM has been identified on the
Italian market, the FreeStyle Libre system (FSL) manufactured by Abbott Diabetes Care. The FSL
does not require daily calibration of the sensor but is unable to send notifications (alerts) in case of
high/low glucose levels. It is intended for self-measurement of glucose levels and is designed for
home-care setting. FSL is composed by a disposable sensor and a reader (dedicated software for
post-analysis and smartphone apps are also available). The FSL sensor is applied to the back of
the upper arm and measures glucose in interstitial fluid for up to 14 days without additional
calibration, updates readings every minute, stores data every 15 minutes, and transmits up to 8
hours of data. The FSL reader holds up to 90 days of data and is provided with a built-in
glucometer that can be used to test blood glucose and blood ketone when necessary.
The manufacturer claims that the FSL is a replacement of SMBG, and patients are able to rely on
the value of glucose given by the sensor for dosing insulin. However, at the same time, within the
instructions for use leaflet, a list of exceptions is reported including times of rapidly changing
glucose levels, for confirmation of hypoglycaemia or impending hypoglycaemia, and if symptoms
do not match the FSL reading. In these circumstances, the use of a blood glucose meter to check
the current glucose readings from the FSL is recommended by the manufacturer. This may appear
contradictory since a fully substitutive technology should not consider the using SMBG at any
point.
33
3.4 Bibliography
Rodbard D. Continuous Glucose Monitoring: A Review of Successes, Challenges, and Opportunities. Diabetes Technol Ther. 2016;18 Suppl 2:S3-S13. Perestelo-Pérez, L., A. Rivero-Santana, B. García-Lorenzo, I. Castilla-Rodríguez and L. Vallejo-Torres (2016). "Efectividad, seguridad y coste-efectividad del sistema flash de monitorización de glucosa en líquido intersticial (FreeStyle Libre®) para la Diabetes Mellitus tipo 1 y 2". Ministerio de Sanidad, Servicios Sociales e Igualdad. Servicio de Evaluación del Servicio Canario de la Salud; Informes de Evaluación de Tecnologías Sanitarias.
34
4. Current use of the technology
4.1 Method
We selected the following Assessment Element:
Assessment Element ID Research question
A0011 What is the diffusion of the technology across Italian Regions?
We collected information about FSL current use in Regions and Autonomous Provinces (Regions
and APs) via the National Network of HTA(RIHTA)’s representatives who were sent a brief
questionnaire on the technology’s use in their systems (Appendix 4). Our first aim was to collect
regional decrees about FSL so that we could comparatively analyse them. In the questionnaire
Regions and APs were asked to state if they provided FSL and, if they did, to send any related
regional decrees and regulations. Other further questions were about authorisation and
stakeholders pressure toward providing the device. We sent a letter and the questionnaire on 26th
June 2017 and asked for a reply within 3 weeks (12th July). After the deadline we reminded
Regions and PAs asking to complete the questionnaire or/and send us a copy/link of related acts
and regulations. To get as a comprehensive as possible overview, we also independently looked on
their web sites for acts, decrees and regulations concerning FSL and used information provided by
Abbott itself on FSL’s spread across Italian Regions and APs.
For the analysis of the regional decrees we extracted a set of variables to compare decisions and
detect any variability. We extracted the following information: types of eligible patients;
prescribers; delivering models; procurement systems, post marketing studies/experimental use
(Appendix 5).
35
4.2 Results
Eight (8) Regions and APs out of 21 sent the questionnaires back on time. Seven stated that they
delivered the technology (all but Valle d’Aosta and Puglia Region) and sent related act and
regulations. Three (3) further Regions and APs sent their regulations but did not fill the
questionnaire after our above-mentioned reminder (Par. 4.1). For the 10 remaining subjects we
used information found on the Regions and APs’ internet websites and provided by manufacturer.
Three regions (Abruzzo, Molise, Sardegna) did not give us any formal feedback nor we could
collect any information via their websites. Only from manufacturers information they result not to
have FSL delivered on public charge. It is thus probable that - at the time of writing (November
2017) - they still have to decide about the technology at stake. As a result, at the present
moment (February 2018) Sardegna, Abruzzo, Molise, Valle d’Aosta and Puglia did not reimburse
the device.
4.2.1 Freestyle in Italian Regions and Autonomous Provinces: resolutions and year of approval
FSL obtained the CE mark in August 2014 and Regions and APs have started to provide it since
2015 – although within the context of e.g. post marketing studies (e.g. Trento Province in 2017).
As to day (November 2017), 16 Regions and PAs out of 21 provide FSL on public charge (see
Table 4.1). 1
Table 4.1 FGM in the Italian Regions. Decrees and resolutions listed by year of approval
REGION RESOLUTION and YEAR
Toscana Delibera Giunta Regionale n. 690 del 25/05/2015 Approvazione progettualità di cure della malattia diabetica in regione Toscana e destinazione. Ripartizione risorse finanziarie a favore della aziende sanitarie toscane al fine di realizzare le progettualità di cura per la malattia diabetica. Delibera Giunta Regionale n. 829 del 30/08/2016 Indicazioni per l'automonitoraggio glicemico per le persone con Diabete e l'utilizzo dei dispositivi per il monitoraggio in continuo del glucosio, dei sistemi di infusione continua dell'insulina e sistemi integrati. Decreto Dirigenziale n. 13639 del 16/12/2016. Indicazioni per l’utilizzo del sistema innovativo FGM “Flash Glucose Monitoring” ai sensi della Delibera 829/2016.
Sicilia Nota Prot. n. 52039 del 24/06/2015 “Avvio progetto pilota sistema FreeStyle Libre” - direttive. Prot. Servizio 8/n.50036 16/06/2017 “Dispositivi monitoraggio del glucosio con sistema Flash Glucose Monitoring (FGM)”.
1The draftof this Report in consultation from 10
th May 2018 to 10
th July 2018 was last updated on Febrauary 2018. So
the list of Regions and APs that introduced the device at stake increased. In fact the producer commented the draft
report highlighting that by June 2018, 3 more Regions and PAs in the meantime provided FSL on public charge (19
Regions and APs out of 21).
36
Emilia Romagna Circolare n.13 del 09/10/2015 “Linee di indirizzo regionali per un uso appropriato dei dispositivi medici per l'autocontrollo e la autogestione nel diabete mellito”.
Basilicata Delibera Giunta Regionale n.452 del 29/04/2016 “Legge Regionale n.9/2010 – approvazione linee guida e di indirizzo per la prescrizione di dispositivi per autocontrollo domiciliare della glicemia”. Integrata successivamente dalla Delibera Giunta Regionale n°430 19/05/2017.
Lazio Determinazione n.G08900 del 03/08/2016 “Linee prescrittive presidi monitoraggio glicemico”.
Umbria Deliberazione Giunta Regionale n. 1411 del 05/12/2016 “Nuove modalità di prescrizione, autorizzazione ed erogazione dei dispositivi erogabili dal Servizio Sanitario Nazionale alle persone affette da diabete mellito”.
Piemonte Linee di indirizzo su flash monitoring, Prot. 592/A1404A del 12/01/2017
Friuli Venezia Giulia Delibera Giunta Reginale n.303 del 24/01/2017 “Linee di indirizzo regionali sulle modalità di prescrizione e gestione del monitoraggio in continuo della glicemia nei pazienti diabetici”.
Campania Delibera Giunta Regionale n.98 28/02/2017 “Presidi diagnostici e terapeutici per pazienti affetti da diabete: provvedimenti”.
PA Trento Deliberazione di Giunta Provinciale n. 340 del 03/03/2017 "Autorizzazione all'APSS ad attuare il progetto di sperimentazione della durata di un anno Indagine clinica post market: valutazione dell'impatto clinico/economico dell'introduzione di un dispositivo medico per il monitoraggio flash del glucosio nella popolazione diabetica della provincia di Trento in trattamento insulinico intensivo DMT1, DMT2, gravidanza".
Calabria
Decreto del Commissario ad ACTA n.146 del 07/11/2017 Approvazione aggiornamento periodico prontuario Terapeutico Regionale (PTR) - Aggiornamento DCA 118/2015 e DCA 93/2016 "Linee guida di appropriatezza prescrittiva per l'utilizzo dei farmaci biologici in area reumatologica, dermatologica e gastroenterologia"- Approvazione "Linee guida in materia di prescrizione e dispensazione a carico del Servizio Sanitario Regionale (SSR) di dispositivi per l'autocontrollo e l'autogestione di soggetti affetti da diabete" - PO 2010-2018 2.4. Area Efficientamento della Spesa -2.4.1.1 "Commissione Terapeutica Regionale e Revisione del Prontuario Terapeutico Regionale (PTR)”. Allegato 3 Linee guida in materia di prescrizione e dispensazione a carico del Servizio Sanitario Regionale (SSR) di dispositivi per l'autocontrollo e l'autogestione di soggetti affetti da diabete).
Veneto Deliberazione Giunta Regionale n. 547 del 28/04/2017 “Erogazione dei dispositivi dell’Automonitoraggio della glicemia che adottano il sistema FGM (Flash Glucose Monitoring). Art.53, l.r. n.30 del 30 dicembre 2016- Collegato alla legge di stabilità regionale 2017- DGR/CR n.26/2017”.
Lombardia Decreto direttore generale n. 7517 del 23/06/2017 e “Giudizio di priorità Freestyle Libre - Sistema di monitoraggio continuo e non invasivo del glucosio nei fluidi interstiziali di pazienti con diabete mellito in trattamento insulinico intensivo. Presa d’atto del documento tecnico approvato dalla commissione per le tecnologie emergenti”.
PA Bolzano Deliberazione di Giunta Provinciale n.793 del 18/07/2017 “Criteri sull'acquisizione di sistemi per il monitoraggio continuo della glicemia e sulla loro erogazione gratuita a favore delle persone affette da diabete”
Marche Deliberazione Giunta Regionale n. 888 del 31/07/2017 “Linee di indirizzo per la prescrizione ed il corretto utilizzo dei Sensori per il Monitoraggio Glicemico in continuo (GCM)”
Liguria
Delibera n.657 del 04/08/2017 “Prescrizione e gestione del monitoraggio in continuo della glicemia nei pazienti diabetici. Funzioni di A.Li.Sa”.
37
4.2.2 Freestyle in Italian Regions and Autonomous Provinces: a comparative description of decisions
In 2015, Tuscany was the first Region to issue a resolution on FSL. It was initially aimed at an
experimental introduction in May 2015 (Delibera 690 25/05/2015) with two projects. The first one
was a cross over randomized trial, comparing FSL with SMBG in T1DM patients aged 14-70 years
in multinjection therapy (defined as 4 or more SMBG per day) and the other for T2DM patients in
multinjection therapy (defined 4 or more SMBG per day) and 40-75 years old. In August 2016
(DGR 829, 30/08/2016) Tuscany authorized the use of FSL (together with other innovative
devices) in its regional health service for T1DM patients in insulin therapy with at least 4 injections
per day (CSII and MDI), pregravidic diabetes, pregnancy planning and T2DM patients with
additional conditions such as frequent episodes and proven/documented hypoglycaemic events, a
persistent glycometabolic failure (HbA1c 10 mmol/mol over the target for at least 6 mouths),
special professional categories (dangerous jobs, musicians, athletes, etc.), patients with conditions
that make finger pricks uncomfortable. In December 2016 Tuscany gave the remit to the ESTAR
(the regional centre for centralised procurement) to start an urgent procedure to acquire the new
system for flash glucose monitoring for almost 10000 potential patients (Decreto Dirigenziale
n.13639).
In Sicilia FGM was first delivered in a pilot project for 6 months to 100 patients with DM1 (60%)
and DM2 (30%) in multi daily injection or CSII therapy and women with gestational diabetes
(10%) (Regional Directive Prot. 52039, 24/06/2015). The device was then introduced in 2017
(Nota Assessorile Prot. 50036, 16/06/2017) for all T1DM and T2DM patients in intensive insulin
therapy and in patient with paediatric age as a priority.
Emilia Romagna in October 2015 (Circolare n.13) issued regional guidelines for appropriate use of
medical devices for diabetes self-monitoring and management. Hybrid systems such as FGM are
indicated for adult diabetes patients in intensive insulin therapy with at least 4 SMBG. Eligibility
criteria for the use of FGM are: HbA1c over the target >64 mmol/mol, >8%, needle phobia,
suspected frequent hypoglycaemic events, unaware hypoglycaemic syndrome. In September 2016
(see Circolare n.12) it decided to start a 2 years post-market, multicentre, prospective, non-
controlled study for the safety and applicability of Flash glucose monitoring system (two research
protocols, one for T1DM adult patients in insulin multinjective therapy and some other additional
clinic parameters and one for diabetic children). In the first step of the project the Region decided
38
to suddenly start the study involving a paediatric population of patients 4-11 years old (n=350).
On this purpose all health trusts General Directors were provided with a specific form for a
homogenous and systematic collection of real world data on the use of the FGM in this type of
patients.
In August 2016 Lazio experimentally introduced FSL for 1 year (for patients in multi injection
therapy in one or more of the following conditions: T1DM, age 4-17 years, frequency of monitoring
glycaemia, HbA1c > 8% in the last 4 measurements in patients under 65 years, 4 SMBG or more
per day, overnight monitoring, daily injections of 3 or more different type of insulins (Determina
Dipartimento Salute e politiche sociali della Regione Lazio n.G08900, 03/08/2016).
Basilicata introduced CGM hybrid systems in 2016 (DGR n.452, 29/04/2016) for T1DM paediatric
patients (4-18 years) in basal bolus therapy. The aforementioned decree was integrated with a
further decree in April 2017 (DGR n.430, 19/05/2017) which provided to extend for 1 experimental
year, the use of the “latest generation devices” for patients over 18 with DM1 diabetes in multi
injection therapy with more than 4 daily measurements of blood glucose.
Veneto introduced FGM in 2017 (DGR n. 547, 28/04/2017) for all diabetes patients aged 4-17
years and adults in insulin basal bolus therapy or continuous insulin infusion that measure blood
insulin 5 times or more per day. They have to be resident or have their home in the region.
Diabetologist prescribes the device after a period in which the patient has successfully attempted
to wear and use it.
Lombardia introduced FGM in 2017 (DGR n. 7517 del 23/06/2017). According to the Decree it was
provided for T1DM and T2DM patients in intensive insulin therapy who had experience with self-
monitoring of blood glucose, are able to wear the device, have been properly informed and trained
for its use within a therapeutic plan written and monitored by the diabetologist. The Decree
recalls and adopts the related Priority Judgement (“Giudizio di priorità”) for the Freestyle Libre
which, in Lombardy Region is issued by a multidisciplinary experts team before any decisions
about technology reimbursement. This Priority Judgement recommends the adoption of FSL for
patients as detailed in the “Recommendations table for application in the Lombardy Health
Service”. Here they recommend adoption for T1DM and T2DM patients requiring intensive insulin
treatment and having actual experience of self-monitoring of capillary blood glucose, which are
able to wear continuously the device, that have been informed and trained for use and
interpretation of system information and as part of a specific treatment plan. Further in the
39
“Identification of criteria for appropriate use: organizational, professional, and outcome
measurement requirements” they suggest to identify targeted interventions on different categories
of diabetic patients (see Appendix 5).
Marche deliberated to provide FGM in 2017 (DGR n. 888, 31/07/2017) for patient with T1DM in
intensive insulin therapy and in some special cases for T2DM intensive insulin therapy patients
with the following conditions: numerous and frequent episodes of unnoticed or severe
hypoglycaemia, patients who cannot notice/report hypoglycaemia events. Patients T2DM with
instable diabetes with more than 10 SMBG per day and a persistent glycometabolic failure (HbA1c
10 mmol/mol for at least 6 months), pregravidic diabetes and pregnancy planning. Patients with
diabetes and inpatient history of ketoacidosis. Marche asks for some indicators to be monitored.
Liguria decided to issue a resolution to provide FGM in august 2017 (DGR n. 657, 04/08/2017).
Eligibility criteria were decided by an ad hoc diabetologic committee: Patients in MDI or CSII with
at least 4 injections per day, and that are included in one of the following group: T1DM, pregnant
diabetic patients and pregnancy planning, gestational diabetes, T2DM patients with one of the
following conditions: documented and frequent episodes of severe hypoglycaemia, HbA1c > 10
mmol/mol over the target for at least 6 months, patients that with particular professions (drivers,
athletic persons etc.), needle phobic patients and patients who cannot self-monitoring blood
glucose. Educational program for involved patients and evaluation of their health after 4-6 months
is also highlighted by the commission.
Umbria in December 2016 (DGR n. 1411, 05/12/2016) deliberated to provide FGM to T1DM
Patients in MDI therapy or CSII; pregravidic diabetes, pregnancy planning; TDM2 with at least one
of the following condition: HbA1c>10 mmol/mol over the target for at least 6 months, documented
and frequent episodes of severe hypoglycaemia, patients that with particular professions
(dangerous jobs, musicians, athletic persons etc.). Educational program for involved patients and
evaluation of their health after 4-6 months is also highlighted by the commission.
Prescription must be done by the diabetologic service and the patient will receive the device from
the Health Trust . Effectiveness and quality of life indicators to be monitored are to be collected in
the patient digital record.
Piemonte issued guidelines on FGM in 2017 and eligibility criteria for the delivery are 1) Patient in
basal bolus insulin therapy and performing more than 150 SMBG per month (5 per day); 2) Patient
in insulin therapy with episodes of hypoglycaemia and severe hypoglycaemia (according to
40
international definition); 3) Patient in insulin therapy who are anxious about hyper/hypoglycaemia
crisis or who are needle phobic; 4) Patient in insulin therapy with job that implies a specific use of
hands.
Friuli Venezia Giulia introduced the device in 2017 for 1 year (DGR n. 303, 24/03/2017 - Allegato
A). The Region provided a list of indicators/thresholds to be monitored and collected to assess if
the device is worth and enhance diabetic patients health status on the aforementioned
parameters. The new system can be used by T1DM patients in MDI or CSII therapy with HbA1c
over 8% notwithstanding a good disease management by the patients, usual practice to count
carbohydrate and 6 SMBG per day, severe, numerous, unawareness, hypoglycaemia events,
therapeutic educational program to use the device.
Bolzano Province introduced the FGM in 2017 (DGP n. 793, 18/07/2017) for all resident patients in
its province, who are in insulin therapy and have DM or temporary DM. The reader and the
patches are distributed free of charge from local health services.
Campania region introduced the FGM in 2017 (DGR n.98, 28/02/2017) for all T1DM patients and
patients monitoring glycaemia a minimum of 4 time per day. The reader and the patches are
distributed free of charge by Hospital’s pharmacies and pharmacies on the territory. It is provided
that costs and prescription modes are monitored by an IT platform.
Calabria region introduced the FGM at the end of 2017 (DCA n.176, 06/11/2017) for patients in
multi injection daily therapy with T1DM age 4-17 years, frequency of monitoring glycaemia of ≥7
time per day and HbA1c > 8% and 3 or more different insulin injections, overnight monitoring,
daily delivering of 3 or more different insulins. The reader and the patches are distributed free of
charge by Hospital’s pharmacies and pharmacies on the territory. It is provided that costs and
prescription modes are monitored by an IT platform.
The Trento Province authorized a 1 year post marketing study in 2017 and, in the light of its
results, it will decide about its delivery or not. In this study it includes T1DM e T2DM patients in
intensive insulin therapy (at least 3 injections and 4 SMBG per day) and for pregnancy. In the
study they included 140 patients age 4-18 and 2100 patients over 18 years.
41
4.3 Discussion of Results We detected a certain amount of variability in identification of eligible patients, in the device
procurement strategies and in delivery methods. Before deciding to purchase the device some
Regions organised post marketing trials to collect real world data and monitor the device’s safety
and use in different populations (e.g. Tuscany, Emilia Romagna, Trento). Study’s protocols, when
available, reveal differences in the length of the studies (6 months-1 years) and in type of
population (T1DM or/and T2DM populations or/and paediatric patients). Other Regions decided to
allow the entering of the device for an experimental period (usually 1 year time) and for a specific
group of eligible patients, providing a list of indicators centres delivering the device have to
monitor. This monitoring, nonetheless, appears to be more comprehensive and formalised in some
Regions (e.g. Umbria) and less in others (e.g. Basilicata, Marche).
Among T2DM subjects entitled to potentially be prescribed with the device, Regions list a series of
clinical parameters patients need to comply that varies from region to region. HbA1c varies from 8
to 10 mmol/mol over the target for at least 6 months, the number of measurements of blood
glycaemia recalled varies from a minimum of 3 to a maximum of 10 times per day, and the
number of injections varies from 3 to 6 per day. Those differences are not so huge from a clinical
point of view. Almost all Regions and APs seem to provide the FSL to T1DM and T2DM if in
intensive insulin therapy at least according to the regional Decrees. Nevertheless some decrees
and related documents are difficult to be interpreted (e.g Lombardy).
Some Regions prefer to provide the device via Hospital pharmacy (Toscana) or territory pharmacy
(Sicilia, Calabria), other by both Hospital and territory pharmacy (Veneto, Campania), some other
by diabetologic centres (Umbria, Provincia di Bolzano) or by health trust (Liguria, Friuli Venezia
Giulia) o health trust pharmacy (Lazio). The prescribing physician is always the diabetologist. In
2014 the FSL had the CE mark and right in 2015 some Regions and APs started to organise post
marketing studies, also involving paediatric patients and pregnant women for which the
authorisation was expanded in January 2017 and July 2017. With the issuing of the National
Decree on the New Essential Levels of Care at the beginning of 2017 (DPCM 12th January 2017 –
Allegato 3)2, Regions and PAs decisions about delivering new systems for the monitoring of
2DPCM 12 gennaio 2017, Definizione e aggiornamento dei Livelli Essenziali di Assistenza. Allegato 3 “Presidi
per persone affette da patologia diabetica e da malattie rare”. Si veda CND (National Medical Device Classification), apparecchio per la misurazione della glicemia: W0201060102 and Z1204011;
42
glycaemia increased, since the above decree allowed new devices for diabetic patients to be within
the public benefits basket that must be provided by all regional health services.
43
5. Clinical effectiveness and safety
5.1 Methods
The AEs of this domain were:
Assessment Element ID Research question
D0005 D0005a: How does the technology affect symptom frequency of the target condition? D0005b: How does the technology affect symptom severity of the target condition?
C0001 What harms are associated with the use of the technology?
C0002 Are the harms related to the exposure to the technology?
D0012 What is the effect of the technology on generic health-related quality of life?
The following PICOD (Population, Interventions, Comparator, Outcomes, Design of studies)
structure was defined for this project:
Population: (a) children aged 4 – 18 with T1DM; and (b) adults with T1DM or subjects with
T2DM requiring insulin treatment.
Intervention: FGM.
Comparator: any other glucose monitoring system (SMBG, RT-CGM)
Outcomes:
o differences in HbA1c o hypoglycaemic events (symptomatic and non-symptomatic) o hospitalization due to hypo/hyperglycaemia o hyperglycaemia and diabetic ketoacidosis (DKA) o adverse events o pain or discomfort related to glucose monitoring o quality of life.
Design of studies: HTA reports, systematic reviews, and randomised controlled trials (RCTs)
or controlled studies.
Electronic searches were performed in September 2017 on PubMed, Embase, and the Cochrane
Library following a search strategy based on the above listed PICOD and related keywords (e.g.
Flash glucose monitoring, Diabetes Mellitus, diabetes, NIDDM, T2DM, T1DM etc.).
44
Data extraction and management
Two review authors independently assessed titles and abstracts of all retrieved citations according
to the defined inclusion criteria.
Assessment of risk of bias in included studies
The methodological quality of each included study was assessed in accordance with the criteria
established by the Cochrane tool for assessing risk of bias [Higgins 2011]. The following domains
for the risk of bias were considered: i) Random sequence generation and allocation concealment
(selection bias); ii) Blinding of participants and personnel (performance bias); iii) Blinding of
outcome assessment (detection bias); iv) Incomplete outcome data (attrition bias); v) Selective
reporting (reporting bias).
Statistical analyses
Meta-analyses were performed. Dichotomous outcomes results were expressed as risk ratio (RRs)
with 95% confidence intervals (CIs). Whereas mean difference (MD) was used when continuous
scales of measurement were used. Heterogeneity was evaluated using a Chi2 test with N-1
degrees of freedom, with an alpha of 0.10 used for statistical significance and with the I2 test
[Higgins 2011]. Sources of heterogeneity were sought by assessing the participants, the
intervention, the comparison group, and the outcomes and by visually assessing the forest plots.
Review Manager (Revman 5.3) was used for data synthesis. Data were pooled using both the
random-effects model and the fixed-effect model to ensure robustness.
5.2 Results
The search strategy launched in the above listed electronic databases provided 270 records. After
removing duplicates, the titles and abstracts of 220 records were screened and 24 records were
identified as potentially relevant papers. Full-text articles excluded, with reasons
were 22 (see Appendix 6). The evaluation of the full-texts of these studies allowed the
identification of two trials [Bolinder 2016; Haak 2017] one of which [Haak 2017] had five
secondary publications [Haak 2016; Haak 2016; Haak 2016; Haak 2016; Haak 2017]. (Figure 5.1)
45
Figure 5.1. Study screening process
PRISMA 2009 Flow Diagram
Records identified through database searching
(n = 270 )
Scre
enin
g In
clu
de
d
Elig
ibili
ty
Ide
nti
fica
tio
n Additional records identified
through other sources (n = 0 )
Records after duplicates removed
(n = 220 )
Records screened (n = 220 )
Records excluded (n = 196 )
Full-text articles assessed for eligibility
(n = 24 )
Full-text articles excluded, with reasons
(n = 22 )
Studies included in qualitative synthesis
(n = 2 )
Studies included in quantitative synthesis
(meta-analysis) (n = 2 )
46
Description of trials
The two included studies were multicentre trials and, while one was conducted in the Sweden,
Austria, Germany, Spain and Netherlands [Bolinder 2016], the second trial was conducted in
France, Germany and UK [Haak 2017]. Haak et al included type 2 diabetes patients on intensive
insulin therapy whereas, Bolinder et al considered subjects who have been with type 1 diabetes for
20 years average. Participants in Bolinder were younger (mean age 43 years) than those in Haak
(mean age 64 years).
Both studies randomised participants to sensor-based flash glucose monitoring system (FreeStyle
LibreTM; Abbott Diabetes Care, Witney, UK) that was worn on the back of the arm for up to 14
days and automatically storing glucose data every 15 min or to self-monitoring of blood glucose
with capillary strips. Primary outcomes of interest were difference in HbA1c between intervention
and control groups at 6 months for Haak and time spent in hypoglycaemia (<3·9 mmol/L <70
mg/dL) for the 14 days preceding the end of the 6 month study period for Bolinder. The time
follow-up was 6 months for both studies. See basic characteristics of included studies at Table 5.1.
Risk of bias
Both studies were at low risk of selection bias as participants were allocated centrally using central
interactive web response system. Given the nature of the interventions participants and
investigators could not be blinded. In terms of blinding, in both trials sensor glucose
measurements were blinded to participants and investigators the first two weeks after
randomisation but not during the remaining period of follow-up. Hence, none of the studies were
immune from performance and detection bias. No concern in terms of attrition or selective
reporting bias were identified. Figure 5.2 summarises review authors' conclusions about each risk
of bias item for the two included trials.
47
Figure 5.2. Risk of bias summary: review authors' judgements about each risk of bias item for each
included study
48
Table 5.1 Basic characteristics of included studies
Study ID
Objective Study design
(country)
Participants Outcomes
Follow up Funding Intervention group
Control group
Primary Secondary Safety endpoints
Haak 2017
To compare the use of novel flash glucose sensing technology with SMBG in participants with type 2 diabetes treated with multi-dose insulin therapy.
RCT, multicentre (UK,France,German)
Type 2 diabetes on intensive insulin therapy
Difference in HbA1c between intervention and control groups at 6 months
-sensor-derived glycaemic measures (from 0 to days 194–208 - frequency of glucose finger-sticks - sensor scans per day (d) system utilization for days 15–208 (defined as the % of data collected, assuming continuous device wear) - change in total daily dose of insulin, body mass index (BMI), weight, and participant questionnaire responses.
- all adverse events -severe hypoglycaemia -hypoglycaemic events - sensor insertion or sensor wear-related symptoms -diabetic ketoacidosis -hyperosmolar hyperglycaemic state episodes - cardiac events.
6 months Sponsorship, provision of study devices, study materials, and article processing charges funded by Abbott. Some authors reported conflict of interest with for profit agencies.
Number: 145 Age: 59.0 ± 9.9
Male: 94 (63%) Duration of
diabetes (y) 17 ± 8
Duration of insulin use (y) 9 ± 6
Number: 75 Age: 59.5 ± 11.0
Male: 56 (75%)
Duration of diabetes (y)18 ± 8
Duration of insulin use (y) 10 ± 7
Bolinder 2016
To assess whether flash glucose-monitoring system compared with self-monitored glucose testing reduce exposure to hypoglycaemia
RCT, multicentre (Sweeden, Austria, Spain, Germany, and the Netherlands)
Patients with type 1 diabetes
Time spent in hypoglycaemia (<3·9 mmol/L [<70 mg/dL]) for the 14 days
preceding the end of the 6 month study period
(days 194–208).
- sensor-derived glycaemic measures (d 194–208), - day 208 HbA1c concentrations - change in total daily dose of insulin from day 1 to day 208 - system utilisation for days 15–208(*) - frequency of glucose finger-sticks and sensor scans
-adverse events -sensor insertion-site symptoms - diabetic ketoacidosis - severe hypoglycaemia events
208 days Funded by Abbott Diabetes. Some authors reported conflict of interest with for profit agencies.
Number: 119 Age: 42 (33–51) Male: 65% Duration of diabetes (yr.): 20 (13–27) Screening HbA1c (%): 6·7 (0·5); Self-reported blood glucose frequency per day 5.4 (2.0)
Number: 120 45 (33–57) Male: 49% Duration of diabetes (yr.): 20 (12–32) Screening HbA1c (%): 6·7(0·6); Self-reported blood glucose frequency per day 5.6 (2.3)
49
(*) defined as the percentage of data collected, assuming continuous device wear
(**) defined as the percentage of data collected, assuming continuous device wear
50
Findings
Difference in HbA1c
Difference in HbA1c between F-CGM and SBGM (D0005a) were evaluated at 180 days in the Haak
2017 trial and at 208 days in the Bolinder 2016 trial. The reduction in HbA1c between study end
and baseline values was detected in both groups with no evidence of difference at end of follow-up
(MD 0.19, 95%CI -1.54 to 1.92; I2 = 0%) (Figure 5.3).
Figure 5.3. Forest plot of comparison: Flash-CGM vs SBGM, outcome: Mean difference in HbA1c.
Participants with symptomatic hypoglycaemia
See Addendum at the end of this report for data not available during the assessment.
Participants with hypoglycaemic adverse events
Hypoglycaemic events (D0005a) were reported in both studies and were defined as <70 mg/dL
glycaemia and in Bolinder an episode was defined further as at least two consecutive readings, at
15 min intervals, outside the predefined glucose range. The proportion of participants with
hypoglycaemic adverse events were similar between the groups (4.5% in the Flash-group and
6.1% in the SBGM group) and there was no evidence of difference (RR 0.62, 95% CI 0.28 to 1.39)
Fig. 5.4).
51
Figure 5.4. Forest plot of comparison: Flash-CGM vs SBGM, outcome: hypoglycaemic adverse events (unit
of analysis: participants with at least one hypoglycaemic adverse event)
Participants with severe hypoglycaemic events
Severe hypoglycaemic adverse events (D0005b) were reported by both trials and were defined as
an event requiring third-party assistance. The proportion of participants with hypoglycaemic serious
adverse events were similar between the groups (1.9% in the Flash-group and 2.0% in the SBGM
group) and there was no evidence of difference (RR 0.92, 95% CI 0.23 to 3.68) (Fig. 5.5).
Figure 5.5 Forest plot of comparison: Flash-CGM vs SBGM, outcome: hypoglycaemic severe adverse events
(unit of analysis: participants with at least one hypoglycaemic severe adverse event)
Participants with adverse events
In Bolinder 276 adverse events or serious adverse events were experienced by 124 participants
whereas in Haak any adverse events were experienced by 161 participants. When the data were
pooled between the two studies, the proportion of any adverse events was 66% in the intervention
Study or Subgroup
Bolinder 2016
Haak 2017
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 0.58, df = 1 (P = 0.45); I² = 0%
Test for overall effect: Z = 0.92 (P = 0.36)
Events
2
13
15
Total
120
149
269
Events
5
8
13
Total
121
75
196
Weight
21.0%
79.0%
100.0%
M-H, Random, 95% CI
0.40 [0.08, 2.04]
0.82 [0.35, 1.89]
0.70 [0.34, 1.48]
Flash-CGM SBGM Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100Flash-CGM SBGM
52
group and 55% in the control group with no statistical difference (RR 1.15, 95% CI 0.98 to 1.34; I2
= 1%) (Fig. 5.6). (C0001).
Figure 5.6- Forest plot of comparison: Flash-CGM vs SBGM, outcome: adverse events (unit of analysis:
participants with at least one adverse event)
Participants with serious adverse events
In Bolinder 10 serious adverse events were experienced by 9 participants whereas in Haak 42
serious adverse events were experienced by 28 participants. The proportion of any adverse events
was 7.8% in the intervention group and 8.2% in the control group with no statistical difference (RR
0.77 95% CI 0.42 to 1.43) (fig. 5.7) (C0001).
Figure 5.7 Forest plot of comparison: Flash-CGM vs SBGM, outcome: serious adverse events (unit of
analysis: participants with at least one hypoglycaemic adverse event)
53
Device related symptoms
In Haak, the authors reported of six intervention participants (3,4%) with nine device-related
adverse events (two severe, six moderate, and one mild) that were treated primarily with topical
preparations gaining complete healing at study end (C0002).
Bolinder reported of 10 participants (10%) experiencing device related adverse events seven of
whom withdrew from the study due to device-related adverse events or repetitive occurrences of
sensor insertion-related symptoms (C0002).
Quality of life
Both studies evaluated quality of life using different instruments. Questionnaires administered
included Diabetes Distress Scale (DDS)[Polonsky 2005], Diabetes Quality of Life Questionnaire
(DQoL)[Group 1988], and Diabetes Treatment Satisfaction Questionnaire (DTSQ)[Bradley 1994]
that were completed at baseline and at day 180 (Bolinder) or at day 194 (Haak). Bolinder
administered also the hypoglycaemia patient questionnaire that used record baseline perception of
hypoglycaemia [Workgroup on Hypoglycemia 2005] (D0012).
In Haak 2017, total treatment satisfaction score for DTSQ (status versus change) was significantly
improved for F-CGM group participants (mean 13.1 ± SE 0.50) compared to the control group
using SBGM (mean 9.0 ± SE 0.72), p < 0.0001. In addition, satisfaction with treatment results
using DQoL demonstrated significant improvement for the F-CGM group ( mean −0.2 ± SE 0.04)
versus the SBGM group (0.0 ± 0.06) (P = 0.0259). However, no evidence of difference were
detected in therms of perceived frequency of hyperglycaemia or hypoglycaemia, emotional burden,
physician distress, regimen distress, and interpersonal distress.
In Bolinder 2016, total treatment satisfaction scores according to DTSQ was improved for the F-
CGM group (mean 13.5) compared to SBGM group using (mean 6.8), (adjusted between-group
difference −0.24 [SE 0.049] (P = 0.0001). The total treatment satisfaction resulted also in favour
of the intervention group (DM 6.1, SE 0.84]; P < 0.0001). No evidence of difference was detected
between the two groups in terms of diabetes quality of life score. Contrary to the Haak 2007’s trial,
in Bolinder 2016 perceived frequency of hyperglycaemia (MD −1·0,SE 0.22; P < 0.0001) were
significantly improved in the F-CGM group compared to the control group. No evidence of
difference were observed in terms of diabetes distress (MD −0·03 [SE 0·089]; P = 0.76) or
hypoglycaemia fear behaviour (0·0 [0.72]; P = 0.98) or worry scores (−1.2 [1.48]; P = 0.42).
54
5.3 Discussion of results
Summary of finding
We identified two studies that evaluated the effect of a novel glucose monitoring system on
hypoglycaemia, one study in adults with well controlled type 1 diabetes [Bolinder 2016] and the
second study in subjects with type 2 diabetes on intensive insulin therapy [Haak 2017]. Both
studies were of moderate quality and included a total of 491 participants. The results indicate that,
compared to the standard approach with self-monitoring of blood glucose, F-CGM device provide
similar reduction in HbA1c as well as similar proportion of severe or non-severe hypoglycaemic
adverse events. FGM appears also to have some advantage in terms of quality of life. Device
related adverse events ranged from 3% to 10% that resolved with complete healing except in two
participants that withdrew from the study. No events related to diabetic ketoacidosis or
hyperosmolar hyperglycaemic state episodes occurred in none of the studies.
Considerations on clinical outcomes
The two included trials had two different primary end-points. Haak 2017’s primary endpoint was
difference in HbA1c change between the groups at 6 months follow-up. This endpoint was also
evaluated by the second trials though it was considered as a secondary outcome. We were able to
pool the data though there was a difference of 28 days between the two trials.
The primary endpoint in Bolinder 2016 was time spent in hypoglycaemia (<3.9 mmol/L [<70
mg/dL])7 for the 14 days preceeding the end of the 6 month study period, i.e., days from 194 to –
208). Mean time in hypoglycaemia changed between the two groups by 1.24 h/day in favour to
FCGM. This outcome was also evaluated in Haak 2017 and results showed significant reductions in
all sensor measures of time spent in hypoglycaemia in favour of F-CGM. The two trials assessed
also number of hypoglycemic episodes that resulted significantly lower in the intervention group
compared to the controls but were observed no differences in total daily doses of insulin or
bolus/basal insulin ratios between the study groups. In our assessment in addition to differences in
HbA1c we privileged clinical events related to hypoglycaemia. We were specifically interested in
analysing differences in proportions of subjects with symptomatic hypoglycaemia (defined as
confusion, visual disturbances, seizures, sweating, or hunger in a person with a glucose level < 3.9
mmol/L), differences in proportions of subjects with ≥ 5 hypoglycaemic symptomatic episodes per
55
week, and differences in proportions of subjects with poorly controlled diabetes (defined as HbA1c
greater than 7.5 or 8.0%) at 3 and 6 months follow-up. These outcomes were not reported in the
original publication. We contacted the authors to obtain the data but unfortunately, we obtained
the data from only one trial [Bolinder 2016]when the assessment of the present report was closed.
Details of this data are in the Addendum.
Having observed that the difference in HbA1c and hypoglycaemic events were similar between the
F-CGM and SMBG, the time spent in hypoglycaemia and the number of hypoglicaemic episodes
<70 mg/dL) registered by the sensor, together with parameters of quality of life become the next
most important patient oriented outcomes. Both trials documented that both studies showed that
total treatment satisfaction score for DTSQ (status versus change) was significantly improved for
participants allocated to F-CGM compared to controls. Part of the explanation may lie in the fact
that the frequency of self-monitoring of glucose decreased in the intervention group sor scanning
compared to the control group where the frequency of self-monitoring was maintained by
participants throughout the study period.
Potential limitations
One important limitation of the evidence regarding F-CGM is its applicability in individuals
diagnosed with severe hypoglycaemia unawareness as both trials excluded subjects with this
condition. Specifically Bolinder 2016’s used a cut-off of HbA1c <7.5% and this may suggest that
participants were highly motivated and successful in their self-management compared with general
populations. Another relevant evidence gap at the time of our assessment was the lack of studies
on paediatric patients or pregnant women. Approval for use of FSL in these specific populations
has been achieved only in 2017 and this implies an update of the evidence status in the near
future. Additionally, head-to-head clinical studies comparing either CGM vs FLS or SMGB vs CGM vs
FLS were unavailable during the time range of our systematic search (September 2017). Several
accuracy studies on the FSL have been published after the completion of the present assessment,
showing a wide range of performance and using difference performance indicators. For example,
values of mean absolute relative difference (MARD), defined as the mean of all percentage errors
between a continuous glucose monitoring system measurements and the reference values
measured by SMBG or Yellow Springs Instrument biochemistry analyser, ranged from 9.56% to
56
15.4% [Mancini G, 2018]. Since assessing the accuracy of the FSL was outside the scope of the
present report, focused on the assessment of the advantages of introducing the FSL in terms of
clinical outcomes, patient perspectives, and costs for the INHS, further analyses and evidence
updates are necessary to make final statements about the use of the FSL in those populations in
which a fine tuning of the insulin dose is necessary to guarantee the actual glycaemic control.
Quality of evidence
In terms of quality the two studies were immune from selection bias as they appropriately
concealed the allocation of participants to the respective groups. Additionally, despite the studies
were unblended, the evidence regarding the outcome “differendce in HbA1c” and “hypoglycemic
events” could not be affected by performance and detection bias as they were objective outcomes.
However, we cannot exclude the possibility that the evidence regarding the outcome “quality of
life” could be influenced by these biases. Another potential bias that might influence the gathered
evidence concerns the reporting bias. Regarding the outcome hypoglycaemia events the authors
reported the difference in mean of hypoglycaemia between the groups but did not report the
proportion of subjects that reported non-syptomatic hypoglycaemia.
Other considerations
We are aware of a trial published on December 2017 [Reddy 2017]. In this trial, 40 subjects aged
≥ 18 years with Type 1 diabetes for 3 years were randomised to CGM or FLS and evaluated change
in time spent in hypoglycaemia as a primary outcome. The population included were high-risk
participants that had history of severe hypoglycaemic event in the preceding 12 months requiring
third-party assistance or had a Gold score of ≥ 4. The authors concluded that CGM more effectively
reduces time spent in hypoglycaemia in people with Type 1 diabetes and impaired awareness of
hypoglycaemia compared with flash glucose monitoring. However, it must be acknowledged the
limited sample size of the trial that may influence the quality of evidence. Additionally, another
study that retrospectively evaluated two included trials diabetes [Bolinder 2016][Haak 2017]
provided new insights on potential risk of developing hypoglycaemia while driving at a ‘safe’
glucose level even though patients complied with blood glucose testing requirements associated
with driving [Rayman 2017]. Results suggest that there is a significant risk of hypoglycaemia within
the 4 h driving ‘window’ of blood glucose testing 2 h before and 2 hours after starting to drive.
57
Conclusion
In summary, compared to SBGM, use of flash glucose sensor system resulted in similar reduction in
HbA1c, similar events rates in hypoglycaemic adverse events, but in reduction of the time spent in
hypoglycaemia, as well as in the number of hypoglycaemic episodes <70 mg/dL registered by the
system; flash glucose sensor system appears to have an advantage in terms of quality of life. Flash
glucose-sensing technology is a device that can safely be used for glycemic management of
diabetic subjects treated with insulin therapy. However, despite the device can reduce the
frequency of standard glucose measurement use we cannot conclude that it can completely replace
the SBGM. Future studies are needed to assess the effectiveness of this technology in patients
with less well controlled diabetes and in younger age groups focusing in patient oriented outcomes.
58
5.4 Bibliography
Bolinder, J.R. AntunaP. Geelhoed-Duijvestijn (2016). "Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial." Lancet 388(10057): 2254-2263.
Bradley, C. (1994). Diabetes treatment satisfaction questionnaire. Handbook of Psychology and Diabetes. B.
C. Chur, Switzerland, Harwood Academic Publishers.
Cobry, E.H. ChaseP. Burdick (2008) "Use of CoZmonitor in youth with type 1 diabetes." Pediatric diabetes 9,
148-151 DOI: 10.1111/j.1399-5448.2007.00268.x.
Group, T. D. R. (1988). "Reliability and validity of a diabetes quality-of-life measure for the diabetes control
and complications trial (DCCT). The DCCT Research Group." Diabetes Care 11(9): 725-32.
Haak, T.H. HanaireR. Ajjan (2016) "Using novel flash glucose-sensing technology for 12 months reduces hypoglycaemia in individuals with type 2 diabetes on intensive insulin therapy." Diabetologia. Conference:
52nd Annual Meeting of the European Association for the Study of Diabetes, EASD 2016. Germany. Conference Start: 20160912. Conference End: 20160916 59, S419-s420 DOI: 10.1007/s00125-016-4046-9.
Haak, T.H. HanaireR. Ajjan (2016) "The impact on quality of life, glucose monitoring frequency and safety of novel glucose-sensing technology used by individuals with type 2 diabetes on intensive-insulin therapy."
Diabetes Technology and Therapeutics. Conference: 9th International Conference on Advanced Technologies
and Treatments for Diabetes, ATTD 2016 Milan Italy. Conference Start: 20160203 Conference End: 20160206. Conference Publication: (var.pagings) 18, A73 DOI: 10.1089/dia.2016.2525.
Haak, T.H. HanaireR. Ajjan (2016) "Use of novel flash glucose-sensing technology to optimise glucose control in individuals with type 2 diabetes on intensive insulin therapy." Diabetes Technology and
Therapeutics. Conference: 9th International Conference on Advanced Technologies and Treatments for
Diabetes, ATTD 2016 Milan Italy. Conference Start: 20160203 Conference End: 20160206. Conference Publication: (var.pagings) 18, A28-a29 DOI: 10.1089/dia.2016.2525.
Haak, T.H. HanaireR. Ajjan (2017). "Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized
Controlled Trial." Diabetes Ther 8(1): 55-73.
Haak, T.H. HanaireR. Ajjan (2017). "Use of Flash Glucose-Sensing Technology for 12 months as a
Replacement for Blood Glucose Monitoring in Insulin-treated Type 2 Diabetes." Diabetes Ther 8(3): 573-586.
Haak, T.H. HanaireR. A. Ajjan (2016). "Use of novel flash glucose-sensing technology to optimise glucose control in individuals with type 2 diabetes on intensive insulin therapy." Diabetes and Therapeutics 18: A28-
A29.
Higgins, J. P. T.D. G. Altman J. A. C. Sterne (2011). Chapter 8: Assessing risk of bias in included studies. In:
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0.
The Cochrane Collaboration, 2011. www.cochrane-handbook.org.
Polonsky, W. H.L. FisherJ. Earles (2005). "Assessing psychosocial distress in diabetes: development of the
diabetes distress scale." Diabetes Care 28(3): 626-31.
Workgroup on Hypoglycemia, A. D. A. (2005). "Defining and reporting hypoglycemia in diabetes: a report
from the American Diabetes Association Workgroup on Hypoglycemia." Diabetes Care 28(5): 1245-9.
Mancini G, Berioli MG, Santi E, Rogari F, Toni G, Tascini G, Crispoldi R, Ceccarini G, Esposito S. Flash Glucose Monitoring: A Review of the Literature with a Special Focus on Type 1 Diabetes. Nutrients. 2018 Aug; 10(8):
992.
59
6. Cost and economic evaluation
We selected the following AEs:
Assessment Element
ID Research question
E0001 Can you identify what types of resources are used when delivering the assessed technology and its
comparators (resource-use identification)?
E0002 Can you quantify what amounts of resources are used when delivering the assessed technology and its
comparators (resource-use measurement)?
E0009 What were the measured and/or estimated unit costs of the resources used by the assessed technology
and its comparator(s)?
E0005 What is(are) the measured and/or estimated health-related outcome(s) of the assessed technology and
its comparator(s)?
E0006 What are the estimated differences in costs and outcomes between the technology and its
comparator(s)?
G0007 What are the likely budget impacts of implementing the technologies being compared?
6.1 Methods
In order to answer the cost and economic research questions, we first performed a literature
search of economic studies to find cost effectiveness analysis and Italian cost data. Moreover we
also gathered costs information from manufacturer’s grey literature/questionnaire and the New
Health Information System (NSIS). On that basis a three years budget impact analysis (2018-
2010) was performed. To estimate the percentage of T1DM and T2DM patients in intensive insulin
therapy who are eligible to use FSL we relied on ISTAT’s diabetes disease prevalence data from
2015 to 2017 available for each Regions and APs. As concern prices we used New Health
Information System (NSIS) selecting “Data bank for monitoring consumption of medical device
directly acquired by Italian NHS” (“Flusso contratti”) that also collects data on medical devices’
quantity and purchasing prices in Italian regions. At present, the database is not yet fed
homogeneously by health service trusts (coverage rates for each Regions and APs is available on
Ministry web site http://www.salute.gov.it/imgs/C_17_pubblicazioni_2679_allegato.pdf).
60
6.2 Results
6.2.1 Analysis of literature
We retrieved one HTA published on August 2017 by the Norwegian Institute of Public Health
(NIPH) [Bidonde 2017]. This was a single technology assessment (STA) report containing Cost
Effectiveness Analysis (CEA) and Budget Impact Analysis (BIA) provided by the manufacturer and
not an original economic analysis.
Our research of economic literature gave no results and we could not retrieve any published
economic studies. Thus we had to rely only on the two studies provided by the manufacturer. One
article was a CEA of FSL for T1DM [Bilir, 2016] and the other was a CEA of FSL for T2DM [Li
2016]. Italian costs that are reported in this analysis are extracted from those two articles (tables
6.1 - 6.3).
Bilir 2016 is a study, funded by Abbott Diabetes Care, on the cost-effectiveness of FSL versus
SMBG for T1DM patients who are receiving intensive insulin treatment in a group of European
countries and in Australia. The authors used an IMS Core Diabetes Model (IMS CDM), an internet
application for cost effectiveness analysis and carried out a simulation on cost effectiveness based
on data from IMPACT trial and other sources. They considered Sweden as a core case but they
also reported cost data and CEA for Italy, Germany, France, Netherlands and Australia. In tables
6.2 and 6.3 are reported data useful for Italian context. The authors included in their analysis
costs, life expectancy and QALYs over 50 year time horizon. The developed model was based on a
cohort of patients aged 18 year or over with well controlled T1DM and treated with a multiple daily
insulin injection or continuous subcutaneous insulin infusion. Patients characteristics reflect those
represented in the IMPACT trial (44 mean age, HbA1c of 6.78% and mean diabetes duration of 22
years). FSL costs are based on manufacturer data while diabetes treatment costs are derived from
national database or published literature. Italian costs were expressed in 2015 currency and
include cost of sensors, strips, lancets, insulin, physician visit and acute events costs [E0001]. Bilir
2016 found that annual T1DM italian cost using FSL was €2,292 in the first year and €2,272 for the
second year and over, while SMBG annual cost was €1,674. Italian cost for acute events was
€1,391 for severe hypoglycaemia events. Results for Italian NHS over 50-years time horizon
showed a total cost of €83,924 (and 12.63 QALYs) for FLS and a cost of €71,595 (and 11.59
QALYs) for SMBG with an incremental cost effectiveness ratio (ICER) equal to €16,008 (that is
under the willingness to pay threshold of €31,000-€96,000) [E0006]. Authors concluded that “FSL
61
may be considered cost-effective for use in T1DM patients with good glycaemic control using
intensive insulin”.
Li 2016 is a study, funded by Abbott Diabetes Care, on the cost-effectiveness of FLS for T2DM
patients who are receiving intensive insulin treatment in Europe. The aim of the study was to
estimate the cost-effectiveness of using FSL versus SMBG for intensive insulin therapy in patients
with type 2 diabetes. The author used an IMS CDM internet application in order to perform the
cost effectiveness analysis and carried out a simulation of cost and effectiveness data from
REPLACE trial and other sources. They considered Sweden as a core case but they also reported
results from Italy, Germany, France and Netherlands. In tables 6.2 and 6.3 are reported data
useful for Italian context. Authors used the IMS CMD to assess the cost and health outcomes for
diabetes treatment including costs, life expectancy and QALYs over 40 year time horizon. The
developed model was based on a cohort of patients aged 18 year or over with poorly controlled
T2DM and treated with a multiple daily insulin injection or continuous subcutaneous insulin
infusion. Patients characteristics reflect those represented in the REPLACE study (59 mean age,
HbA1c of 8.70% and mean diabetes duration of 17.5 years). FLS costs are based on manufacturer
data while all other costs are derived from national database or published literature. Italian costs
were expressed in 2015 currency and include cost of sensors, strips, lancets, insulin, physician visit
and acute events costs [E0001].
Li 2016 found that annual T2DM cost using intervention was €3,068 in the first year and €3,048
for the second year and over, while SMBG annual cost was €2,274. Italian cost for acute events
was €1,391 for severe hypoglycemia events. Results for Italian NHS over 40-years time horizon
showed a total cost of €97,891 (and 5.93 QALYs) for FSL and a cost of €86,822 (and 5.40 QALYs)
for SMBG with an incremental cost effectiveness ratio (ICER) equal to €20,968 (that is under the
willingness to pay threshold of €31,000-€96,000) (E0009). Authors concluded that “FSL may be
considered cost-effective for use in T2DM patients receiving intensive insulin”.
62
Table 6.1 General information from retrieved studies (Italian data)
Table 6.1. General information from retrieved studies -continuing
Study Outcomes Effectiveness Time Horizon Discounting
Bilir 2016 FM-SMBG Costs; ICER/QALY LYs/QALY Over 50 years 4% (for both cost and clinical outcomes)
Li 2016 FM-SMBG Costs; ICER/QALY LYs/QALY 40 years 3% (for both cost and clinical outcomes)
Study Country Year of data information
Objective Type of analysis
Perspective Intervention Comparator Population
Bilir 2016
Europe, Australia
NR To estimate the cost effectiveness of using FSL vs SMBG through the IMS Core Diabetes model for intensive insulin treated T1DM patients for Europe and Australia.
Cost- effectiveness
Italian National health service
FSL SMBG People aged 18 or over with well controlled T1DM and HbA1c of <7.5% and treated by multiple daily injection of insulin or continuous subcutaneous insulin infusion for a minimum of six months [data from IMPACT Trial or published literature]
Li
2016
Europe NR To estimate the cost-
effectiveness of using FM vs. SMBG through the IMS Core Diabetes Model for intensive insulin-treated T2DM patients in Europe.
Cost-
effectiveness
Italian
National health service
FSL SMBG People aged 18 or over with poorly
controlled T2DM and HbA1c of >7.5% and <12% treated by multiple daily injection of insulin or continuous subcutaneous insulin infusion for a minimum of six months [data from REPLACE Trial or published literature]
63
Table 6.2: Resources used [E0001]
Study Resource use identification Resource use mesaurement Resource use evaluation (Italy)
Currency/Years
Bilir 2016
Annual FM/SMBG cost; Acute events costs FM: 26 sensors per year; 182.5 back up blood glucose test strip per year; 267.4 lancets per year; 45.8 units of insulin per day; one additional physician visit in the first year. SMBG: 1,971 strips per year; 657,6 lancets per year; 38.4 units of insulin per day.
NR €/2015
Li 2016 Annual FM/SMBG cost; Acute events costs FM: 26 sensors per year; 109.5 back up blood glucose test strip per year; 251.85 lancets per year; 85.2 units of insulin per day; one additional physician visit in the first year. SMBG: 1,095 strips per year; 459.9 lancets per year; 87.8 units of insulin per day.
NR €/2015
64
Table 6.3: Cost and cost effectiveness results [E0009-E0006]
Study Cost results Effectiveness Incremental cost effectiveness ratio
Bilir 2016 Annual FM cost (year 1) €2,292 Annual FM cost (year 2+) €2,272 Annual SMBG cost (year 1+) €1,674 Key acute events costs: €1,391 Base case scenario (over 50 year time Horizon) FM costs: €83,924 SMBG costs: €71,595
LYs FM: 20.24 QALYs FM: 12.63 LYs SMBG: 20.33 QALYs SMBG: 11.59
ICER/QALY: €16,008 [WTP ICER/QALY threshold: €31,000 - €96,000]
Li 2016 Annual FM cost (year 1) €3,068 Annual FM cost (year 2+) €3,048 Annual SMBG cost (year 1+) €2,274 Key acute events costs: €1,391 Base case scenario (over 50 year time Horizon) FM costs: €97,891 SMBG costs: €86,822
LYs FM: 13.62 QALYs FM: 5.93 LYs SMBG: 13.61 QALYs SMBG: 5.40
ICER/QALY: €20,968 [WTP ICER/QALY threshold: €31,000 - €96,000]
65
6.2.2 Budget Impact Analysis (G0007)
Estimates on eligible patients using FSL for each Italian Region and the methods used are reported
in Appendix 7. Figure 6.1 shows the estimates of the total number of T1DM and T2DM patients in
intensive insulin therapy in Italy in the years 2017-2020.
Figure 6.1: Estimates of T1DM e T2DM patients in intensive insulin therapy (Italy 2017-2020)
Fonte: Agenas su dati ISTAT
As concern prices, we used information provided by manufacturer and data from Flusso Contratti
(2017). From the latter we extracted the sensors’ quantity, price (VAT excluded) and the economic
value of the 9 Regions and PAs (Campania; Emilia Romagna; Lazio; Lombardia; PA Trento;
Piemonte; Toscana; Umbria; Veneto). We found that the prices provided by the manufacturer
corresponded to the ones we elicited from Flusso Contratti. Based on the above we calculated the
mean cost per patient considering an average of 26 sensors per patient per year (one sensor lasts
fourteen days, so an average of two sensors per months is needed to treat one patient) (Table
6.4). We considered only sensor’s price because in the regions with available data, the reader and
a number of strips related to the use of FSL are provided free of charge. If addional strips per
months are required more than those free provided by Regions/APs or included in the device,
addional cost should be considered in the impact of the use of the FSL. The variability of prices for
each region is shown in figure 6.2. The higher price for sensor is €49.00 in two regions (Emilia
Romagna and Friuli Venezia Giulia) whereas the lowest is €32.75 in two regions (Sicilia and
Campania) and consequently they have respectively the highest and the lowest mean cost per
patient per year ranging from €851.50 to €1,274.00 (Table 6.4 and Figure 6.3). Considering the
economic value of each region-manufacturer agreement, derived from Flusso Contratti or regional
250.000
260.000
270.000
280.000
290.000
300.000
310.000
320.000
330.000
2017 2018 2019 2020
T1DM
T2DM
66
decrees and resolutions, Toscana has an economic agreement value that accounts for about
6,000,000 euros (table 6.4) followed by Veneto with an agreement of €1,213,308.
Table 6.4: Sensors’ price and quantity
Regions Sensor price (VAT excluded)
Quantity Purchasing agreement value
Mean cost per
patients
Basilicata* € 45.00 NR €1,170.00
Calabria* € 35.00 NR €910.00
Campania € 32.75 40,986 €1,342,291.50 €851.50
Emilia-Romagna € 49.00 3,967 €194,383.00 €1,274.00
Friuli-Venezia Giulia*
€ 49.00 NR €1,274.00
Lazio € 35.00 5,328 €186,480.00 €910.00
Lombardia € 35.00 12,188 €426,580.00 €910.00
Marche* € 42.00 NR €1,092.00
PA Trento € 36.00 1 €36.00 €936.00
Piemonte € 42.00 300 €12,600.00 €1,092.00
Sicilia* € 32.75 NR €851.50
Toscana € 35.00 171,428 €5,999,980.00 €910.00
Umbria € 42.00 2,400 €100,800.00 €1,092.00
Veneto € 36.00 33,703 €1,213,308.00 €936.00
Totale 270,301 €9,476,458.50
Fonte: Agenas su dati NSIS-(Flusso contratti and Manufacturer information–2017) *Region for which we have no information
Figure 6.2: Sensor regional Price (2017)
Fonte: Agenas su dati NSIS- Flusso contratti and Manufacturer data
€ 30,00 € 32,00 € 34,00 € 36,00 € 38,00 € 40,00 € 42,00 € 44,00 € 46,00 € 48,00 € 50,00
67
Figure 6.3: Mean cost per patient (2017)
Source: Agenas based on NSIS-Flusso Contratti
On the basis of recorded data from Flusso Contratti and applying a mean price of €37.00 for
those regions without information available, we calculated the mean cost per patient per each
region. We thus estimated the expenditure for 2018-2020 broken down per T1DM and T2DM. The
estimates were calculated considering a minimum of 5% and a maximum of 100% of patients
treated with FSL. We found variability in price set by manufacturer and regions and thus in
expenditure estimates. Manufacturer stated that the price differs from region to region according
to the quantity of eligible population and eligibility criteria set by each single region. Table 6.5 and
Table 6.6 show respectively the estimates in expenditure for T1DM and T2DM patients from 2018
to 2020. The provided estimates are reported here as a useful tool for Italian Regions and APs in
order to have an idea of the potential impact on their regional budgets. We finally calculated the
total estimated amount of expenditure for all years (table 6.7 - 6.8). A broadest analysis that
includes other percentages of population treated and estimates in expenditure is reported in
Appendix 7.
€800,00 €900,00
€1.000,00 €1.100,00 €1.200,00 €1.300,00 €1.400,00
Mean cost per patient
68
Table 6.5: Estimated expenditure for FreeStyle Libre for T1DM (min-max)
DM1 2018 2019 2020
Regions Expenditure (5% patients)
Expenditure (100% of patients)
Expenditure (5% patients)
Expenditure (100% of patients)
Expenditure (5% patients)
Expenditure (100% of patients)
Abruzzo* € 401,577 € 8,031,547 € 436,216 € 8,724,332 € 473,807 € 9,476,148
Basilicata € 277,667 € 5,553,359 € 303,559 € 6,071,197 € 331,810 € 6,636,200
Calabria € 691,813 € 13,836,263 € 677,178 € 13,543,575 € 662,683 € 13,253,661
Campania € 1,304,471 € 26,089,422 € 1,200,208 € 24,004,170 € 1,103,996 € 22,079,920
Emilia-Romagna € 1,397,382 € 27,947,650 € 1,348,007 € 26,960,148 € 1,300,111 € 26,002,234
Friuli-Venezia Giulia € 345,622 € 6,912,441 € 334,312 € 6,686,254 € 323,345 € 6,466,911
Lazio € 1,738,701 € 34,774,035 € 1,730,433 € 34,608,668 € 1,722,001 € 34,440,036
Liguria* € 365,078 € 7,301,572 € 376,176 € 7,523,526 € 387,535 € 7,750,703
Lombardia € 2,197,389 € 43,947,790 € 2,250,394 € 45,007,895 € 2,304,504 € 46,090,087
Marche € 350,308 € 7,006,161 € 331,325 € 6,626,515 € 313,357 € 6,267,145
Molise* € 69,168 € 1,383,373 € 65,139 € 1,302,798 € 61,329 € 1,226,589
PA Bolzano* € 93,503 € 1,870,070 € 101,855 € 2,037,104 € 110,918 € 2,218,364
PA Trento € 70,876 € 1,417,520 € 62,095 € 1,241,904 € 54,404 € 1,088,098
Piemonte € 995,236 € 19,904,731 € 915,907 € 18,318,150 € 842,839 € 16,856,796
Puglia* € 1,083,729 € 21,674,589 € 1,053,203 € 21,064,063 € 1,023,395 € 20,467,912
Sardegna* € 429,638 € 8,592,774 € 445,953 € 8,919,061 € 462,770 € 9,255,400
Sicilia € 1,310,995 € 26,219,919 € 1,329,588 € 26,591,763 € 1,348,462 € 26,969,250
Toscana € 863,684 € 17,273,686 € 892,196 € 17,843,936 € 921,504 € 18,430,085
Umbria € 323,683 € 6,473,666 € 353,450 € 7,069,002 € 385,940 € 7,718,815
Valle d'Aosta* € 23,053 € 461,079 € 20,688 € 413,766 € 18,564 € 371,295
Veneto € 1,000,752 € 20,015,056 € 1,012,585 € 20,251,715 € 1,024,476 € 20,489,524
Italia € 15,334,335 € 306,686,712 € 15,240,477 € 304,809,551 € 15,177,759 € 303,555,183
Note: *Region for which we have no information
69
Table 6.6: Estimated expenditure for FreeStyle Libre for T2DM (min-max)
2018 2019 2020
Regions Expenditure (5% patients)
Expenditure (100% of patients)
Expenditure (5% patients)
Expenditure (100% of patients)
Expenditure (5% patients)
Expenditure (100% of patients)
Abruzzo* € 325,277 € 6,505,553 € 353,335 € 7,066,709 € 383,784 € 7,675,680
Basilicata € 224,911 € 4,498,221 € 245,883 € 4,917,669 € 268,766 € 5,375,322
Calabria € 560,368 € 11,207,373 € 548,514 € 10,970,295 € 536,773 € 10,735,465
Campania € 1,056,621 € 21,132,432 € 972,168 € 19,443,378 € 894,236 € 17,884,735
Emilia-Romagna € 1,131,879 € 22,637,596 € 1,091,886 € 21,837,719 € 1,053,090 € 21,061,809
Friuli-Venezia Giulia € 279,953 € 5,599,077 € 270,793 € 5,415,865 € 261,909 € 5,238,198
Lazio € 1,408,348 € 28,166,968 € 1,401,651 € 28,033,021 € 1,394,821 € 27,896,429
Liguria* € 295,713 € 5,914,273 € 304,702 € 6,094,056 € 313,903 € 6,278,069
Lombardia € 1,779,885 € 35,597,710 € 1,822,819 € 36,456,394 € 1,866,648 € 37,332,970
Marche € 283,749 € 5,674,990 € 268,373 € 5,367,477 € 253,819 € 5,076,387
Molise* € 56,026 € 1,120,532 € 52,763 € 1,055,266 € 49,676 € 993,537
PA Bolzano* € 75,737 € 1,514,757 € 82,502 € 1,650,055 € 89,843 € 1,796,875
PA Trento € 57,409 € 1,148,191 € 50,297 € 1,005,942 € 44,068 € 881,359
Piemonte € 806,141 € 16,122,832 € 741,885 € 14,837,701 € 682,700 € 13,654,005
Puglia* € 877,820 € 17,556,417 € 853,094 € 17,061,891 € 828,950 € 16,579,009
Sardegna* € 348,007 € 6,960,147. € 361,221 € 7,224,439 € 374,843 € 7,496,874
Sicilia € 1,061,906 € 21,238,134 € 1,076,966 € 21,539,328 € 1,092,254 € 21,845,092
Toscana € 699,584 € 13,991,686 € 722,679 € 14,453,588 € 746,418 € 14,928,369
Umbria € 262,183 € 5,243,670 € 286,294 € 5,725,892 € 312,612 € 6,252,240
Valle d'Aosta* € 18,673 € 373,474 € 16,757 € 335,150 € 15,037 € 300,749
Veneto € 810,609 € 16,212,195 € 820,194 € 16,403,889 € 829,825 € 16,596,515
Italia € 12,420,811 € 248,416,236 € 12,344,786 € 246,895,736 € 12,293,984 € 245,879,698
Note: *Region for which we have no information
70
Table 6.7: Estimated total expenditure (3 years) T1DM
Regions 5% of patients 100% of patients
Abruzzo* € 1,311,601 € 26,232,028
Basilicata € 913,037 € 18,260,757
Calabria € 2,031,674 € 40,633,499
Campania € 3,608,675 € 72,173,513
Emilia-Romagna € 4,045,501 € 80,910,032
Friuli-Venezia Giulia
€ 1,003,280 € 20,065,606
Lazio € 5,191,137 € 103,822,740
Liguria* € 1,128,790 € 22,575,801
Lombardia € 6,752,288 € 135,045,772
Marche € 994,991 € 19,899,822
Molise* € 195,638 € 3,912,760
PA Bolzano* € 306,277 € 6,125,539
PA Trento € 187,376 € 3,747,523
Piemonte € 2,753,983 € 55,079,678
Puglia* € 3,160,328 € 63,206,566
Sardegna* € 1,338,361 € 26,767,236
Sicilia € 3,989,046 € 79,780,933
Toscana € 2,677,385 € 53,547,709
Umbria € 1,063,074 € 21,261,485
Valle d'Aosta* € 62,307 € 1,246,141
Veneto € 3,037,814 € 60,756,296
Italia € 45,752,572.35 € 915,051,447.05
Note: *Region for which we have no information
Table 6.8: Estimated total expenditure (3 years) T2DM
Regions 5% of patients 100% of patients
Abruzzo* € 1,062,397 € 21,247,942
Basilicata € 739,560 € 14,791,213
Calabria € 1,645,656 € 32,913,134
Campania € 2,923,027 € 58,460,545
Emilia-Romagna € 3,276,856 € 65,537,126
Friuli-Venezia Giulia € 812,657 € 16,253,141
Lazio € 4,204,820 € 84,096,419
Liguria* € 914,319 € 18,286,399
Lombardia € 5,469,353 € 109,387,076
Marche € 805,942 € 16,118,856
Molise* € 158,466 € 3,169,335
PA Bolzano* € 248,084 € 4,961,687
PA Trento € 151,774 € 3,035,494
Piemonte € 2,230,726 € 44,614,539
Puglia* € 2,559,865 € 51,197,318
Sardegna* € 1,084,073 € 21,681,461
Sicilia € 3,231,127 € 64,622,555
Toscana € 2,168,682 € 43,373,644
Umbria € 861,090 € 17,221,803
Valle d'Aosta* € 50,468 € 1,009,374
Veneto € 2,460,630 € 49,212,600
Italia € 37,059,583 € 741,191,672
Note: *Region for which we have no information
71
Figure 6.4: Expenditure (estimates) T1DM (3 years)
€ 50.000,00
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Figure 6.5: Expenditure (estimates) T2DM (3 years)
6.3 Discussion of results
Regarding economic studies there is an uncertainty in results that are supported by the NIPH HTA
report conclusion on the use of FSL. NIPH HTA report tried to evaluate the manufacturer’s CEA
based on Norwegian data. Nonetheless eventually NIPH’s authors could not validate the
manufacturer’s economic model since they were not allowed to change the inputs nor to have
information on the assumptions underpinning the model. Authors further observed that there was
uncertainty in efficacy data because they were taken from several studies, different countries and
different target populations that were not representative of Norwegian population. In addition
several input data were judged as old and generating possible results’ overestimates. Considering
the duration of effects at 6 months, NIPH asserted that long term effects of treatment should be
considered in the economic model as they can affect the efficacy data uncertainty. Although the
model (IMS CDM) used by the manufacturer is a credible tool, NIPH concluded that the cost
effectiveness estimates are not reliable for the reasons stated above. As regard to budget impact
analysis we created a model in order to support regional decision process. We found that there is
€ 50.000,00
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73
variability in price set by manufacturer in each region, but we cannot justify it in terms of
differences in quantity purchased or differences in patient eligibility.
74
6.4 Bibliography
Bidonde J, Fagerlund BC, Frønsdal KB, Lund UH, Robberstad B. FreeStyle Libre flash glucose self
onitoring system: a single‐technology assessment. Norwegian Institute of Public Health
(Folkehelseinstitutttet). Oslo: Norwegian Institute of Public Health, 2017.
Bilir SP, Li H, Wehler EA, Hellmund R, Munakata J. Cost effectiveness analysis of a flash glucose
monitoring system for type 1 diabetes (T1DM) patients receiving intensive insulin treatment in
Europe and Australia. Value Health 2016;19 (7):A697‐A8.
Hellmund R, Budget Impact Analysis of a Flash Glucose Monitoring System for People with Type 2
Diabetes who are using Intensive Insulin. Poster presented at the International Society for
Pharmacoeconomics and Outcomes Research (ISPOR) 19th Annual European Congress, 29
October–2 November 2016, Vienna, Austria.
Li H, Bilir SP, Wehler EA, Hellmund R, Munakata J. Cost effectiveness analysis of a flash glucose
monitoring system for type 2 diabetes (T2DM) patients receiving intensive insulin treatment in
Europe. Value Health 2016;19 (7):A698.
75
7. Patients’ and social aspects
Assessment Element ID Research question
H0006 How do patients and/or important others using the technology react and act upon the technology?
7.1 Method
We translated and adapted the Patient Group Submission Template for HTA of Health
Interventions (not medicines) [HTAi, 2015; Facey et al, 2017] by the International Society of HTA
in order to grasp information on benefits and limits of the use of the technologies from patients’
perspective. Patients Associations (PAs) involved to fill the template were pointed out via a public
call and suggested by the clinical experts collaborating to the present rapid report. A public call
was published on Agenas’ web site on 30th June 2017 asking diabetes PAs to submit an
application to be involved in this report. We received requests from 7 PAs plus the 5 ones clinicians
had pointed out (Appendix 8). We ended up with a list of 12 PAs who were sent a letter explaining
the assessment’s aims with slides presenting the research protocol of the rapid HTA on FGM and
the adapted Template about positive and negative aspects of different glucometers (Appendix 9).
The Template contained two main open ended questions. The first asked to list positive and
negative aspects of three different modalities to self-measuring glucose levels in a domiciliary
setting, while the second was about the presence of any group of patients experiencing problems
with one modality or another. We also asked basic information about the responding PA such as
funds and financing, level of action, presence of physicians in their organigrams. Below we provide
an aggregated synthesis of the FGM, RTCGM and SMBG’s positive and negative aspects gathered
from PAs Template’s answers. An Analysis of written material was done and sentences reported by
three different PAs which referred to a same positive or negative characteristics, were aggregated
in a sole category.
76
7.2 Results
7.2.1 Patient Associations responding to the Template
Three out of the 12 PAs eventually sent us the filled questionnaire. One of them sent additional
material such as a report of a survey on FSL use they had performed among people with diabetes.
The 3 PAs responding were umbrella associations which aggregated many other diabetes
associations at local level. One is a national association gathering together more than 60 PAs
throughout Italy, the other two are regionally based and gather 18 and 23 local APs. All of the
three umbrella associations declared to represent type 1 and 2 diabetes and both adult and
paediatric patients. All were financed by patients’ annual associations’ fees and private donations,
while none provided physicians in their organigrams, but declared to involve them when
necessary.
7.2.2 Patient Associations’ perspectives on different types of glucose self-
measurement
7.2.2.1 Flash Continuous Glucose Measurements Systems
We identified various categories of positive and negatives aspects (Table 7.1). According to the
responding PAs, FGM can enhance the management of diabetes disease enhancing social life and
interaction at school and in other social contexts, particularly for children. This device is told to be
more easily accepted by e.g. teachers at the school as it can, for example, avoid children to be
taken out the room during lessons to measure glycaemic levels. For some professional categories,
such as musicians, it can prevent pain related to the daily routine of finger pricking or can avoid
some professional categories to stop working in order to finger prick. Among FGM’s negative
aspects PAs quoted the absence of nocturnal alarms, particularly for those patients who cannot
detect hypoglycaemic crisis and/or for monitoring children glucose levels during night without
waking up. Furtherly sensors can sometimes detach before the stated two weeks.
77
Table 7.1 - FGM: patients views on positive and negative aspects
Positive aspects Negative aspects
1. Better disease management 2. Better knowledge of oneself diabetes disease
3. Less Accountable measurements than SMBG but more valuable in the display of glycemic trends
4.
5. Better social life for children and their caregivers 6. Sensors can detach before the provided time (e.g. due to water or sweat)
7.
8. Particular useful for specific categories of patients (disabled patients) and for professional categories (musicians, sport etc.)
9. Autocalibration’s problems(first day of use it is not accountable) - Sometimes many hours before calibration is done (until 48 h)
10.
11. Less number of finger pricks 12.
13. Measurements are enough accountable 14. Differences between values on glucometers and FGM cannot be entered and corrected as the system cannot be calibrated
15. Discreet 16. No alarms
17.
18. Very wearable (small) 19. Expensive
20. Easy to insert and use 21. It underestimates low values (<100) and it can induce not useful corrections
22. 23. After some months some people can have site reaction were sensors are inserted also after many days and not right after its insertion
24.
25. 26. It can generate anxiety
27. 28. Not accountable if variations are quick
Additional material sent by Patients Associations about FGM
One PAs sent a report based on a survey they made on acceptability FGM/FSL.. Subjects
participated on a voluntary basis and filled a self-administrated on line questionnaire, so final
results have limitations related to sampling and biases (e.g. people who do not use the internet).
Collection of data lasted from 1st March to 29th March 2017. Subjects with diabetes (or their
carers) who responded to the questionnaire were 529, of which the 67% declared to be resident in
Lombardy Region. Authors final observations are several, but since this quantitative survey have
no statistical validity (online questionnaire filled on a voluntary basis) and conclusions cannot be
inferred to the whole diabetic population (e.g. older people)., nonetheless they can give an idea of
patients perceptions about FSL. Bearing this in mind and with this limitations explicated, one of the
authors’ conclusion is about satisfaction with the device which results to have a very high score
(8.8 on 10 scale).
78
7.2.2.2 Real Time Continuous Glucose Measurements Systems
Two APs highlighted that RT-CGM has all the positive aspects of the FGM but besides it has also
alarms for hypoglycemic crisis, which seem to be important for most of the diabetic patients but it
would need to be more discrete. In addition RT-CGM can be connected to a Continuous System for
Insulin Injection (CSII), can be inserted in different parts of the body and gives immediately
available data to be used by patients. Nonetheless it is a quite big device to be weared and it is
usually provided just to the patients who uses CSII and not as a stand-alone device. Also in the
case of RT-CGM sensor’s patch comes off too easily.. Prescription by diabetologist and education
for its use are highlighted among negative aspects for the RT-CGM, perhaps since FGM can be
bought freely by patient and seems to be more user friendly (Table 7.2). Nonetheless the need of
education and training in the use of FGM can be found in producer’s guidelines.
Table 7.2 - RT-CGM and Patients views positive aspects and negative aspects
Positive aspects Negative aspects
All the positive aspects of FGM In some models the alarm is too much invasive
Alarms (important for people who cannot detect hypoglycemic symptoms and for children during night to prevent hypoglycemic events)
More difficult to be inserted in the body
Some model have the possibility to be connected with Insulin Pump (Sensor Augmented Pump)
It is a quite big device to be weared (wearabilty problems)
Detailed and quick reports on glycemic profiles Needs to be prescribed by the diabetologist
Can be inserted in different parts of the body Needs A structured therapeutic educations for use*
Safe and accountable Expensive and not reimbursed if it stands alone and can be
reimbursed just u fine uses the CSII pump.
Gives real time and immediately available data to be used by patients
In some cases the sensor’s patch comes off too easily
Needs 2 hours before calibration
Can generate anxiety
In both RT and FGM sensors can detach and both need education of the patients for their use,
although this is perceived as lesser needed in case of the FGM.
7.2.2.3 Self Monitoring of Blood Glucose
The self-monitoring of blood glucose levels by finger pricking is told to be more accurate and
precise but more invasive. SMBG seems not to be perceived as an alternative or a comparator to
CGM. The comparison is mainly done between RTCGM and FGM, while SMBG is said to be, of
79
course, more invasive although more accurate in detecting sugar in blood. It is something that
cannot be avoided, although number of pricking can be reduced.
Table 7.3 - Patients views on SMBG
Positive aspects Negative aspects
Data on blood’s glycemic levels are accurate and precise
Many finger sticks are painful
It is easy to use if it has auto calibration Some models needs a bigger blood drop and this can be uncomfortable
Different models allow personalization of care (e.g. more acceptable models for children at school, some models can be seen in distance by parents or don’t have biological debris, other models helps patients to calculate basal bolus etc)
If temperature is very high or very cold they could not work
accurate and accountable measuraments Patients cannot easily access to the models that fit their personal characteristics
Helps to understand if therapy is correct and allows therapy decision. In t1dm is necessary.
You do not have models for blind people During night cannot be used
7.2.2.4 Special groups of patients
Flash Glucose Measurements Systems
According to the responding PAs special groups of patients can benefit from FGM. Children and
their carers: parents do not have to wake up their child to measure level of glucose to avoid
nocturnal hypoglycaemia, which are common in patient treated with insulin. At school children do
not need to exit the room to measure glucose and this can make the monitoring easier for them
and their carers. Elderly with cognitive impairment and senile dementia can be more easily
monitored several times avoiding most of the finger pricks. Specific professional categories who
cannot stop to monitor their glucose, or need to avoid the pain of many finger pricks (e.g.
musicians etc).
Real Time Continuous Glucose Measurements Systems
RT-CGM is useful for DM1 patients and children and their parents to monitor glucose without
waking up as an alarm will advise them in case of nocturnal hypoglycaemia. Alarm are a positive
aspects – and their absence in the case of FGM is pointed out as a cons - although APs highlight
that alarms are better when they are not too loud or too noisy. This RTCGM gives a major control
80
over ones diabetes and can prevent hypoglycaemic events also before their symptoms are too
heavy. Some professional categories that cannot easily eat in a proper way and count their
carbohydrates and for all the people who need a CGM that can be connected with a continuous
insulin infusion pump (FGM cannot be connected) and patients very educated to self-management
of their disease. In patients with T2DM as a whole both F and RT CGM are highlighted as device
that can generate anxiety who are not in insulin therapy.
Finger Pricks
Cannot monitor continuously the glucose, although their measurements are the golden standard as
are on blood and not on interstitial liquid. It is fine for all the people who are not familiar with
technologies (e.g. elderly people etc.)
7.3 Discussion of results
Measurement of glycaemia via SMBG is perceived by all PAs as being more accurate and precise
and their answers reveals that the perceived comparator of FGM is RT-CGM, as they both measure
interstitial glucose levels.Both for FGM and RT-CGM the responding associations list positive and
negative aspects. Particularly, two of the responding PAs highlighted that RT-CGM has all the
positive aspects of FGM plus alarm etc. (see Table 7.2.1). In fact a problem that PA highlighted
for RT systems was that in some Regions, it is more difficoult to have it prescribed as a stand-
alone device. Our responding PAs list the absence of alarm as a FGMs shortcoming, particularly
for those categories of patients that cannot be aware of hypoglycaemic symptoms and during
night have to handle probable hypoglycaemic crisis which must be detected without counting on
alarm. Yet a negative aspect can always be seen also as an advantage according to patient’s
characteristics. For example responding APs highlights there are patients that do not feel
comfortable with alarm for its noise (see Table 7.2.1) or feels that do not have to set an alarm
transforms his/her daily work and normalises the self-perception of this disease (Fritz Mathieu et
al, 2017). Patients’ preference and needs, given that RT-CGM and FGM have both pros and cons,
will matter on final decision provided that effectiveness and safety are equal and the devices are
appropriately prescribed by the diabetologist.
81
7.4 Bibliography
Fritz Mathieu A, Guillot C, Diabetes self-monitoring devices and transformations in patients work, 20174 Vol.11, n°4, pp. k-ao Karen Facey, Helle Ploug Hansen and Ann single Eds. “Patient Involvement in HTA”, Springer
Nature Singapore Pte Ltd., 2017
Patient Group Submission Template for HTA of Health Interventions (not medicines) https://htai.org/interest-groups/pcig/resources/for-patients-and-patient-groups/
82
8. Conclusions
From a clinical point of view, independent studies are necessary, which also consider outcomes
such as quality of life in the use of the device and that evaluate the FSL versus the other RT-CGM
systems on the market. A desirable study design could be one that allows the comparison of the
three methods (SMBG, CGM and FLS). In fact, the SMBG still represents a necessary self
monitoring modality for patients in intensive insulin therapy, since a capillary control is necessary
for therapeutic decision in specific situations, when the goal is to obtain a real optimization of
glucose control. Moreover, given that the indications for use of FSL have been recently extended
to paediatric patients and pregnant women, an update of the evidence will be necessary in the
near future to assess its impact in these populations. To date it has been found that the FSL is
widespread in the Italian territory and already most of the Regions and PA have purchased it,
often within controlled frameworks and according to patients’ eligibility criteria that are not always
completely homogeneous. The price of the device and targeted population are the two main
variables for determining the potential financial impact of the FGM systems. From the patient's
point of view, the two non-capillary blood glucose detection systems seem to have both positive
and negative aspects, from which emerges the importance of being able to make a shared choice
with the doctor of the glycemic control mode that is best suited to specific patient life conditions,
also in order to reduce the burden of disease management.
83
APPENDIX 1 - The Agenas adaptation of the EUnetHTA Core
Model ®
Health Technology Assessment (HTA) is the multidisciplinary evaluation of one or more health
interventions in their context of use. Since 2006 Agenas has been involved in the E uropean HTA
network EUnetHTA (http://www.eunethta.eu/contactus/all/356/all). EUnetHTA’s main aim is to
increase collaboration and avoid inefficiencies and duplications by using shared, standardised and
agreed methods. These in a continuous development cycle. One of the methods produced and
used is the HTA Core Model ® (http://meka.thl.fi/htacore/BrowseModel.aspx). The idea behind the
Model is the provision of a standard method for HTA evidence synthesis, structuring and
presenting in a standard format to facilitate its use by network agencies and others.
The Core Model is divided into domains which represent the various aspects of the assessment of
health technologies’ research. Each domain contains a series of research questions or Assessment
Elements (AEs). Ver 2.0 of the EUnetHTA Core Model is divided into domains:
1. Health problem and current use of technology (CUR)
2. Description and technical characteristics of technology (TEC)
3. Safety (SAF)
4. Clinical effectiveness (EFF)
5. Costs and economic evaluation (ECO)
6. Ethical analysis (ETH)
7. Organisational aspects (ORG)
8. Social aspects (SOC)
9. Legal aspects (LEG)
While using the Core Model in both Joint Actions 1 and 2 with the European Commission, Agenas
identified some recurring common problems with the Core Model requiring further development
work if the Model were to be used in the production of Health Technology Assessment reports in
Italy.
The problems are mainly AEs repetition, partial or complete overlap of AE content and likely
answers, as well as lack of definition and clarity.
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As a consequence Agenas undertook its own review of the Model to streamline its use and
increase its relevance to everyday work of both HTA doers and HTA users. The Model basis for the
review was version 2.0, medical and surgical intervention application.
The review process included a visual inspection of the 104 AEs with linked clarifications to identify
any likely overlaps. The second phase consisted in grouping all AEs related to a unique concept
(such as informed consent, technology and comparator(s) descriptions, regulatory information,
mortality as a burden of illness measure, mortality as an outcome measure) into the likeliest
domain of relevance. Agenas also attempted to link some of the text of each AE’s clarification note
more closely with the AE and corrected any English syntax problems. In addition a single AE
containing multiple questions was divided into sub questions. All original AE identifiers were
maintained to denote the origin of the AE. To make identification of the information quicker and
unpack some domains, Agenas also introduced two new domains REG or Regulatory Information
and HAZ or Environmental Hazard for the assessment of possible harms not directly caused to the
technology’s recipient.
Agenas started using its Core Model adaptation for the 2014-2015 crop of Agenas HTA reports.
Although some Agenas HTA reports are adaptations to Italy of up to date reports produced
elsewhere or updates of previous Agenas work. In these cases the Agenas Core Model adaptation
use will be partial. Agenas plans to evaluate and develop the Model further.
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APPENDIX 2 – List of Assessment Elements
Assessment Element
ID
Research question
A0001 A0001a:For which health condition is the technology proposed?
A0001b: Which group of patients represents the target population for the technology?
A0001c: For what purposes is the technology used?
A0006 What are the statistics of incidence, prevalence, morbidity, and mortality of the health condition?
A0011 What is the diffusion of the technology across Italian Regions?
B0001b What is(are) the comparator(s)?
B0005b In what context and level of care is(are) the comparator(s) used?
B0001 What is this technology?
B0003 What is the phase of development of the technology?
B0004 How is the technology used?
B0005 In which setting and level of care is the technology used?
B0007 Does the technology require additional/special equipment/tools or accommodation?
B0009 What disposables and supplies are needed to use the technology?
F0001 F0001a: Is the technology new/innovative?
F0001b: Is the technology an add-on, a replacement or a modification of the standard mode of care?
E0001 Can you identify what types of resources are used when delivering the assessed technology and its
comparators (resource-use identification)?
E0002 Can you quantify what amounts of resources are used when delivering the assessed technology and its
comparators (resource-use measurement)?
E0009 What were the measured and/or estimated unit costs of the resources used by the assessed technology
and its comparator(s)?
E0005 What is(are) the measured and/or estimated health-related outcome(s) of the assessed technology and
its comparator(s)?
E0006 What are the estimated differences in costs and outcomes between the technology and its comparator(s)?
G0007 What are the likely budget impacts of implementing the technologies being compared?
H0006 How do patients and/or important others using the technology react and act upon the technology?
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APPENDIX 3 – Manufacturers involvement tools and
procedure
Methods
The manufacturers of flash continuous glucose monitoring (FGM) systems were invited to
contribute to the assessment in the early stages of preparation by providing relevant information.
Manufacturers’ attention was asked to notify their interest by responding to a call on the Agenas
website.
Individual face-to-face meetings between the authors and manufacturers were held to present the
project objectives and describe terms of collaboration. Manufacturers who did not respond to the
web notice were not involved further.
During the meetings, manufacturers were informed that all the material shared with the authors
before, during, and after the meeting (information and data) should not be confidential and could
be published in the final document. Confidential information was not requested and, if given, would
not be used for the assessment.
A structured questionnaire (Table A2.1) was developed by the authors and sent to each responding
manufacturer, before the meeting, to gather information on: the health condition addressed by the
technology, standard of care for the condition, technical characteristics of the technology, current
use of the technology, regulatory aspects, published/ongoing clinical studies, registries, costs data,
and economic evaluations performed. Up to three weeks were given to the manufacturers to fill
and return the questionnaire.
Results
One manufacturers of FGM systems responded to the Agenas call and agreed to meet the authors’
team: Abbott Diabetes Care. The company was the only having an FGM system on its products
portfolio.
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Table A2.1: Questions for the manufacturer of FreeStyle Libre (Abbott Diabetes Care)
Health problem and current use of technology
Which group(s) of patients represents the target population for FreeStyle Libre System?
Which other devices or therapies can be considered as the main comparators of FreeStyle Libre System?
Are there specific ICD9-CM (ICD10-CM) codes that identify the use of the FreeStyle Libre System (and comparators) in
the hospital discharge database or in other national databases?
As of today, how many of your FreeStyle Libre System have been used in Italy? How many around the world?
As of today, how many Italian Regions use FreeStyle Libre System? (Please specify if private or public providers).
Description and technical characteristics of technology
What is the current phase of development of the model on the market?
How many versions/evolutions of the device have been launched to the last version?
In case of two or more versions, could you describe the differences between the [n] generations of your device?
What is the risk classification of the FreeStyle Libre System?
Could you please describe the principle of action and the main characteristics of the FreeStyle Libre System?
What is/are the indication(s) of use of the FreeStyle Libre System? Does the system indications cover all types of
diabetes?
What are the warnings, precautions, contraindications for the use of the FreeStyle Libre System?
What disposables and supplies are needed to use the FreeStyle Libre System?
Does the technology require specific equipment/tools?
- If yes, please provide descriptions and CND (Classificazione Nazionale Dispositivi medici) codes for all of them.
Are there similar devices/therapies/procedures that can be considered as “competitors” of the FreeStyle Libre System?
(please specify device names and manufacturers)
Could you please provide instructions for use document (IFU) for the FreeStyle Libre System?
Regulatory aspects
Has the FreeStyle Libre System obtained the CE mark?
- If yes, When? (please report month and year)
Has the FreeStyle Libre System been approved by the FDA?
- If yes, when? (Please report month and year)
- If not, please report details on the FDA approval status (if any).
When was the FreeStyle Libre System launched in Italy? And which is/are the registration number(s) on the medical
devices’ repertory of the Italian Ministry of Health?
What is the reimbursement status of the FreeStyle Libre System in Italy?
Are you aware of any difference in the reimbursement of the FreeStyle Libre System across the Italian regions?
- If yes, please provide specific regional reimbursement status.
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Are you aware of any difference in the reimbursement of the FreeStyle Libre System across Europe?
- If yes, please provide specific national reimbursement status.
Clinical Effectiveness and Safety
Are there comparative clinical studies (on humans) published/ongoing aimed to compare FreeStyle Libre System versus
other treatments? (if yes, please provide full references)
Are there non-comparative clinical studies (on humans) published/ongoing aimed to report on effectiveness and safety of
FreeStyle Libre System? (if yes, please provide full references)
Is there any register for data collection and patient’s follow-up?
- If yes, who runs it? (please specify web-link and/or key-person name and e-mail address)
Can you specify the ID number(s) of the ongoing trial(s)?
Costs and economic evaluation
What is the list price of FreeStyle Libre System? (please, indicate the price, VAT excluded, for all the equipment needed
for the implantation procedure)
Please fill the table with all the relevant items for a single procedure (Item; Number of units; Price per unit VAT
excluded).
What is the real cost of FreeStyle Libre System (VAT excluded)?
Are there economic evaluation studies published/ongoing reporting on FreeStyle Libre System? (if yes, please report full
references)
Organisational aspects
Which professionals decide on the use of FreeStyle Libre System?
Which professionals (nurses, doctors, and other professionals) use FreeStyle Libre System? Describe the staff involved in
terms of skills and number of units.
Is there the need of training for the patient or his caregiver?
- If yes, who provides it?
- How much does this training cost and who funds it?
How does the procedure using FreeStyle Libre System differ from the standard of care in terms of need of
additional/special equipment/tool, complexity, dedicated human resources?
Patient and Social Aspects
Which specific groups of patients may benefit from FreeStyle Libre System and why?
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APPENDIX 4
Questionnaire sent to Regions’ representatives from the
National Network for HTA (RIHTA – Rete Italiana per l’HTA)
Agenzia Nazionale per i Servizi Sanitari Regionali
IX ACCORDO HTA Agenas - Ministero della Salute
Rapid HTA Report “Sistemi Flash per il Monitoraggio della Glicemia nei
soggetti diabetici in terapia insulinica”
USO CORRENTE e DIFFUSIONE DELLA TECNOLOGIA
Area introduttiva – DATI IDENTIFICATIVI REGIONE
Nome e Cognome del compilatore ___________________________________________________________
Ufficio di appartenenza ____________________________________________________________________
Posizione ricoperta _______________________________________________________________________
Contatto telefonico _______________________________________________________________________
Indirizzo e-mail ___________________________________________________________________________
USO CORRENTE e DIFFUSIONE DELLA TECNOLOGIA
(da compilare a cura della Regione)
1.Nelle Aziende sanitarie del territorio regionale viene erogata la tecnologia FGM/FreeStyle Libre?
2. L’utilizzo dell’FGM/FreeStyle Libre è stato autorizzato dalla Regione?
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3. Può inviare copia della Delibera regionale o della/e Determina/e aziendale/i con cui si è autorizzato
l’utilizzo di questo presidio?
4. Ove non citati nei provvedimenti inviati, indicare le fonti informative utilizzate a supporto
dell’autorizzazione (Parere esperti, HTA, altro), la spesa prevista e l’eventuale tariffa (in caso di
distribuzione mediante le farmacie territoriali).
5. Indicare se l’autorizzazione è stata concessa su istanza:
□ di azienda/e sanitaria/e
□ del produttore
□ di associazioni di pazienti
□ di professionisti sanitari
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APPENDIX 5 – Extraction and analysis of regional decrees on FGM
Normativa di
riferimento
Tipo di diabete Condizione di acquisto
Lombardia DGR n. 7517 del 23/06/2017 - Giudizio di priorità Freestyle Libre -
DM1 e DM2 Trattamento insulinico intensivo. Esperienza di automonitoraggio della glicemia capillare. In grado di indossare in maniera continua il dispositivo. Adeguatamente formati e informati su uso del dispositivo e su come interpretarne le informazioni (Piano diabetologico da parte del medico diabetologo); nel Conclusioni (p.6) Introduzione nuova tecnologia Si raccomanda l’adozione del FreeStyle Libre per pazienti con diabete di Tipo 1 e di Tipo 2 che necessitano di trattamento insulinico intensivo, che abbiano avuto effettiva esperienza di automonitoraggio della glicemia capillare, che siano in grado di indossaredi continuo il dispositivo, che siano stati adeguatamente informati e formati per l’utilizzo e per la interpretazione delle informazioni prodotte dal sistemanell’ambitodi un piano di trattamento specifico redatto e monitorato da un medico diabetologo. Il piano dovrebbe comprendere: - la indicazione di uso del FreeStyle Libre quale: A) integrazione del SMBG con punture multiple, oppure: B) sostituzione del SMBG (fatte salve 25 strisce fornite dal produttore del dispositivo); - la programmazione di controlli per la verifica dell’impatto sugli obiettivi di ottimizzazione metabolica Identificazione di criteri per uso appropriato: requisiti organizzativi, professionali, di processo, di misura dell’esito. In analogia alle considerazioni riportate per l’automonitoraggio della glicemia capillare negli Standard di Cura AMD-SID, si suggerisce di individuare interventi mirati su diverse categorie di pazienti diabetici: 1. Paziente in trattamento dietetico e/o con farmaci che non causano ipoglicemia: nessuna indicazione a FreeStyle Libree altri dispositivi per monitoraggio non invasivo del glucosio interstiziale (FGM), né a sistemi di monitoraggio continuo del glucosio in “real-time” con sistemi
di allarme di stato e predittivi(RTCGM). 2. Paziente in trattamento con ipoglicemizzanti orali secretagoghi che ha già presentato episodi di ipoglicemia o che è ad alto rischio di ipoglicemia clinicamente significativa: se col monitoraggio SGBM il paziente raggiunge e mantiene una condizionedi stabilità, nessuna
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indicazione a FGM o RTCGM; solo in caso di soggetti a persistente elevato rischio di ipoglicemia col solo monitoraggio SGBM è ipotizzabile la fornitura di FreeStyle Libre in parziale sostituzione del SMBG, assicurando comunque la verifica su sangue capillare prima di ciascun provvedimento terapeuticoe utilizzando una fornitura di almeno 25 strisce/mese assicurata dal produttore del FreeStyle(con possibile estensione in situazioni particolari su giudizio clinico riportato nel piano di trattamento specifico). 3. Paziente in trattamento insulinico non intensivo o in trattamento combinato con farmaci non insulinici orali o iniettivi: ipotizzabile fornitura di FreeStyle Libre in parziale sostituzione del SMBG; si conferma peraltro la necessità di verifica su sangue capillare prima di eventuali provvedimenti terapeutici (utilizzando la fornitura di 25 strisce/mese garantita dal produttore del FreeStyle). 4. Paziente in trattamento insulinico intensivo (basal-bolus o con microinfusore): in assenza di controindicazioni, e su indicazione di centro specialistico accreditato, indicazione all’uso di sistema di monitoraggio continuo Real-Time (RTCGM) completodi funzioni di allarme (di stato e predittivi). Solo in caso di non praticabilità di questa soluzione (per mancata accettazione del paziente, limiti organizzativi del centro specialistico, altro) è raccomandabile la fornitura di FreeStyle Libre in aggiunta un monitoraggioSMBG intensificato (sempre con la verifica su sangue capillare prima di eventuali provvedimenti terapeutici). In questo tipo di indicazionepuò essere considerata una riduzione dellafornitura di strisce reattive tale da garantire comunque un controllo capillare al risveglio e prima dei pasti principali, necessario per la definizione del bolo insulinico prandiale, più una media di 2 strisce/die per controllo di dati anomali del FreeStyle Libre(in totale 150 strisce/mese).
Toscana DGR n.829 del 30/08/2016 DGR n. 690 25/05/2015 (allegato F) Decreto dirigenziale n.13639 del 16/12/2016 e relativi allegati.
DM1 e DM2; diabete pregravidico e programmazione della gravidanza. In trattamento insulinico intensivo (almeno 4 iniezioni di insulina die). Con terapia MDI o Microinfusore. Pazienti DM2 con almeno una delle seguenti condizioni: persistente scompenso glicometabolico (HbA1 10 mmol/mol oltre il target , per almeno 6 mesi) - pazienti con ipoglicemie ripetute e documentate; Categorie particolari di pazienti e con condizioni che rendono difficile o impediscono la digitopuntura)
Procedura negoziata senza pubblicazione di bando (art 63 comma 2 del D.lgs 50/2016)- INFUNGIBILITA'. Fornitura dispositivo in abbonamento 35 euro. Ogni 3 mesi. PERIODO 12 MESI PER
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Umbria DGR n. 1411 del 05/12/2016
DM1 in terapia insulinica multiniettiva o CSII; DM2 con almeno una delle seguenti condizioni aggiuntive (HbA1 10 mmol/mol oltre il target per almeno 6 mesi; pazienti con ipoglicemie ripetute e documentate, categorie particolari come sportivi, musicisti, lavori con esposizione al pericolo, o che complicano la regolarità dei pasti e/o dell). Diabete pregravidico e programmazione della gravidanza (per trand glicemico postprandiale e notturno non sostituisce però il monitoraggio capillare); Per il DM1 è specificato che il trattamento è insulinico intensivo (se intensivo è sempre anche multi iniettivo?) ma non per il DM2; Con terapia MDI o Microinfusore. Categorie particolari di pazienti e con condizioni che rendono difficile o impediscono la digitopuntura).
Basilicata DGR n. 430 del 19/05/2017 (a integrazione del DGR n. 452 del 29/04/2016)
DM1 in insulinica intensiva multiiniettiva (MDI) solo adulti sopra i 18. rilevazione routinarie superiori a 4 volte al giorno. Con terapia MDI o Microinfusore
Trento Reg.delib. 340/2017 3 marzo 2017; finanziato con delibera di giunta provinciale 2413 20 dicembre 2016 su finanziamento SSP 2017-2019.
DM1 e DM2 intensivo e gravidanza (nel trial allegato questa popolazione non è però citata). In trattamento insulinico intensivo (almeno 3 iniezioni di insulina die e almeno 4 controlli al giorno). Nel trial è inclusa la popolazione pediatrica. Sono stati coinvolti 140 pazienti dai 4 ai 18 e 2100 oltre i 18 anni. Prevista educazione terapeutica all’utilizzo e monitoraggio degli aspetti clinici, etico sociali, economici e qualità vita baseline e a 3-6 mesi.
Piemonte Linee di indirizzo regionali sul FGM, Prot. 592/A1404A classificazione: 14.110.40
1) Insulino trattati in basal bolus con più di 5 misurazioni SMBG die. 2) insulino trattati con passaggio in DEA per ipoglicemia o precedente ipoglicemia severa (secondo definizione internazionale). 2) insulino trattati con ansia da iper/ipo o agofobie 3)insulino trattati con attività lavorativa che impedisce un agevole controllo capillare dei polpastrelli.
Veneto DGR n.547 del 28/04/2017
Diabete mellito. bambini/adolescenti dai 4 ai 17 anni. Adulti in terapia insulinica basal-bolus che effettuano abitualmente 5 o più determinazioni di glicemia al giorno. MDI, Iniettori di insulina a penna. Il diabetologo verifica di idoneità e l'aderenza alla nuova tecnologia
attraverso l'applicazione di un sensor di prova. Lo stesso fornisce un percorso strutturato di educazione al paziente sull'uso dei dispositivi di automonitoraggio della glicemia che adottano il sistema FDG.
5600 pz stimati. Prezzo per ciascun sensore €36 + 4%iva. E' inoltre previsto un
costo di distribuzione pari a €6+22%iva. (informazioni tratte dal questionario)
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Sicilia Nota Assessorile Prot. 50036 del 16/06/2007 Provvedimento transitorio
DM1 in pazienti in età evolutiva. Demandando, ad una fase successiva, l'estensione agli altri pazienti.
Viene demandato alla Centrale Unica di committenza regionale l'accertamento di disponibilità sul mercato del dispositivo.
Bolzano Delibera Provincia Autonoma n.793 del 18/07/2017
Diabete mellito o diabete temporaneo in possesso di un'esenzione (013 o 013T). MDI (numero di strisce reattive e lancette pungi dito ridotta a 100 pezzi)
I sistemi sono acquistati dall'Azienda Sanitaria dell'Alto Adige
Emilia Romagna
Circolare n.13 del 09/10/2015, Linee di indirizzo regionali
Nei pazienti 4-11 anni DM1. Diabete mellito negli adulti. Paziente in trattamento insulinico intensivo (basal-bolus o con microinfusore). Si raccomanda che l'utilizzo del Flash monitoring sia gestita da Centri diabetologici nei pazienti in terapia insulinica intensiva con autocontrollo glicemico convenzionale su almeno 4 punti/die, in cui sia già stato attivato un programma di ETS che permetta al paziente stesso di modificare la propria terapia insulinica sulla base dei dati glicemici raccolti con il sistema in uso, agli alimenti introdotti ed all'attività fisica programmata e che presentino almeno uno dei criteri indicati: - HbA1c non a target, cioè con valori >64mmol7mol 8>8%) - agofobia - sospette ipoglicemie frequenti, ipoglicemie notturne o sindrome da ipoglicemie inavvertite
(unawareness)
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Liguria DGR n.657, 04/08/2017 Nella delibera inviata non sono specificate caratteristiche cliniche etc. Lo sono in un altro documento NON allegato alla delibera ma fatto dalla commissione diabete e inviato da G. flego su richiesta nostra • DM 1 • Diabete pre-gravidico e programmazione della Gravidanza • Gravidanza in DM precedentemente noto • DM 2 solo se (almeno 1 condizione): 1. Ipoglicemie ripetute e documentate 2. HbA1c > 10 mmol/mol oltre il target per almeno 6 mesi 3. Pazienti con lavori o professioni con evidente esposizione al pericolo (autisti, muratori, sportivi, ecc) 4. Agofobici e Pazienti con oggettive difficoltà nell’esecuzione del SMBG
?
Marche DGR n.888 31/07/2017 Pazienti DM1 in terapia insulinica multiettiva e in casi eccezionali in pazienti DM2 con terapia insulinica intensiva. DM2 episodi ripteuti di ipoglicemie inavvertite e severe; pazienti con ridotta capacità di segnalare le ipoglicemie (es. bambini di etàinferiore ai 6 anni); pazienti con diabete instabile che richiede più di 10 controlli glicemici al giorno; persistente scompenso glico-metabolico (HbA1c 10 mmol/mol poltre il target poer alemno 6 mesi; diabet pregravidico e programmazione gravidanza; pazienti condiabete noto ed episodi di ricovero e chetoacidosi
Lazio Determina G08900 del 3/08/2016
Pazienti diabetici in terapia multi-iniettiva che si trovano in una o più delle seguenti condizioni: - diabete di tipo 1; - età pediatrica (4-17); Nella richiesta del materiale per l'automonitoraggio è prevista una verifica di idoneità del paz in termini di aderenza alla terapia e al percorso educativo di rinforzo (scarico dati documentato in cartella) e la riduzione di 1 punto di HbA1c nel caso in cui il pz si trovi nella condizione 3 dei criteri stabiliti. - glicemie capillari/die >= 7 (da PT su piattaforma webcare e/o scarico dati su supporto informatico) - HbA1c stabilmente > 8% nelle ultime 4 determinazioni in pazienti con età < 65 anni; - necessità di controllo notturno della glicemia (discrepanza non atrimenti spiegata fra autocontrollo domiciliare e HbA1c) - somministrazione giornaliera di 3 o più insuline diverse
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FVG DGR n. 303 del 24/02/2017 e il suo Allegato A "Documento per la prescrizione e gestione del monitoraggio in continuo della glicemia dei pazienti diabetici"
Il nuovo sistema FGM può essere utilizzato nei pazienti diabetici di tipo I in terapia multiiniettiva o con microinfusore che presentano: − HbA1c con valori maggiori a 8% nonostante l’ottimizzazione della terapia e la buona gestione da parte del paziente; − pratica abituale della conta dei CHO e almeno 6 rilevazioni routinarie al dì della glicemia; − ipoglicemie gravi, ripetute, inavvertite; − inserimento in un programma di educazione terapeutica strutturata che permetta al paziente stesso di utilizzare al meglio il sistema in uso, raccogliendo correttamente i dati, modificando la propria terapia insulinica sulla base dei dati glicemici raccolti in maniera strutturata della dieta e della attività fisica. Il medico prescrittore è responsabile dell’avvio di tale programma e della valutazione nel tempo.
Campania DGR n.98 del 28/02/2017 DM1 e pz diabetici che eseguono almeno 4 controlli al giorno
Calabria Decreto del Commissario ad ACTA (DCA) n.176 del 06/11/2017 (All.3 Linee guida in materia di prescrizione e dispensazione a carico del Servizio Sanitario Regionale (SSR) di dispositivi per l'autocontrollo e l'autogestione di soggetti affetti da diabete)
Recepire l’innovazione tecnologica, introducendo l’utilizzo del nuovo dispositivo per l’automonitoraggio della glicemia FGM (Flash Glucose Monitor) e del dispositivo I-port per i pazienti in terapia multi-iniettiva. Poiché l'FGM non possiede allarmi per iper- o ipo-glicemie e non è adatto all’impiego in pazienti con ipoglicemie inavvertite. Si raccomanda l’uso del Flash Glucose Monitoring secondo una o più delle seguenti condizioni: - Diabete di tipo 1 - Età pediatrica (4-17) - Glicemie capillari/die ≥7 HbA1c stabilmente > 8% nelle ultime 4 determinazioni in pazienti con età < 65 anni - Necessità di controllo notturno della glicemia (discrepanza non altrimenti spiegata fra autocontrollo domiciliare e HbA1c) - Somministrazione giornaliera di 3 o più insuline diverse.
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Modalità di acquisto
Modalità di distribuzione Introduzione sperimentale e/o controllata per periodo
Numero pazienti stimati e metodologia per la stima
Lombardia - ?
Toscana Solo tramite centrale unica (ESTAR)
Farmacie Ospedaliere (decreto dirigenziale 13639 del dicembre 2016)
si 100
Umbria Cras Umbria Salute (centrale unica)
Prescritto dal servizio diabetologico e distribuito dal competente servizio della ASL di residenza. L’acquisto definitivo avviene dopo un periodo di prova da parte del paziente.
Indicano una serie di indicatori per il monitoraggio dei efficacia e QoL dei dispositivi ad alta tecnologia (tutti raccoglibili con la cartella informatizzata).
Basilicata ? ? Si dichiara introduzione per 1 anno da maggio 2017 in via sperimentale. Ma non vi sono indicatori di monitoraggio, negli eventuali trial.
Trento Progetto "Indagine Clinica Post Marketing" della durata di 1 anno, alla cui conclusione verrà decisa o meno l’introduzione/uso del device.
Piemonte Dati desunti dal registro regionale diabete del Piemonte si stima che il numero di potenziali pazienti riferibili alla categoria 1 sia di 7942. Per quanto attinente alla categoria 2, dati italiani recentemente stimati, indicano 1530 soggetti di tipo 1 e 1620 soggetti di tipo 2 con precedenti di ipoglicemia severa. Le rimanenti categorie hanno un numero limitato di soggetti.
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Veneto La distribuzione avviene tramite le Aziende ULSS tramite le farmacie pubbliche e private convenzionate utilizzando la piattaforma Web DPC.
Sicilia Distribuzione attraverso le farmacie territoriali
Bolzano Attualmente i sistemi
FGM sono offerti gratuitamente all'Azienda Sanitaria dalla ditta produttrice
Distribuzione diretta da parte
dell'Azienda Sanitaria tramite il servizio di diabetologia
Emilia Romagna
Liguria Tramite ALISA Erogazione direttamente dalle aziende socio sanitarie
? ?
Marche Indica una serie di indicatori da monitorare una
volta introdotto il device.
Nel 2016 nei centri di diabetologia sono stati
seguito 59031 pazienti diabetici. 45188 DM2 ; 2785 DM1; 1372 diabete gestazionale; 9686 altro (pediabete etc)
Lazio L'erogazione avviene trimestralmente a cura dei servizi farmaceutici delle ASL di residenza
Verifica trimestrale dell'andamento della prescrizione e delle criticità mediante la compilazione di un foglio elettronico. Il servizio farmaceutico monitora la spesa trimestralmente.
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Friuli Venezia Giulia
L'erogazione ai pazienti avviene tramite azienda sanitaria
Introduzione sperimentale di 1 anno a partire da febbraio 2017. La valutazione sulla prosecuzione della erogazione a carico del SSR a 12 mesi sarà effettuata sulla base dei dati relativi ai pazienti in terapia da almeno 6 mesi. La valutazione del raggiungimento degli obiettivi per singolo paziente a 6 e 12 mesi viene effettuata dal centro prescrittore. Qualora l’utilizzo del CGM o sistema ibrido non apportasse benefici in termini metabolici o personali al paziente, allora non deve essere continuato. Indicatori: riduzione e mantenimento per sei mesi (secondo le rilevazioni al follow up ogni 3-4 mesi) della HbA1c di almeno 5.5 mmol/moli (0,5%); - documentata riduzione degli episodi ipoglicemici gravi (definiti come gli episodi di glicemia < 70 mg/dl nei quali l’individuo presenta uno stato di coscienza alterato e necessita dell’aiuto o della cura di terzi per risolvere l’ipoglicemia) (45); - riduzione della glicemia media; - riduzione della % di valori di glicemia superiori al target glicemico; - aumento della % di valori di glicemia compresi nel target glicemico (definito come 70-180 mg/dl); - riduzione della % di valori di glicemia inferiori a 70 mg/dl; - riduzione degli eventi di glucosio basso; - riduzione della durata media (espressa in ore) trascorsa in ipoglicemia; - aderenza dei pazienti al programma di cura (controlli e follow up).
.
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Campania Attraverso la Centrale unica di acquisto Soresa
Distribuzione tramite farmacie territoriali e/o ospedaliere delle Aziende del SSR
Monitoraggio dei costi delle modalità di prescrizione attraverso la piattaforma SANIARP
Calabria Sconto del 55% sul prezzo di listino. Sulla base di quanto stabilito dal DCA n. 124 del 11 Ottobre 2017, avente OGGETTO: “Approvazione Schema Accordo Regione Calabria - Federfarma Calabria per l’attuazione della Farmacia dei Servizi”.
La richiesta del dispositivo di lettura e del materiale di consumo viene compilata dal diabetologo una volta l’anno dopo aver verificato le condizioni per la prosecuzione dell’utilizzo. L'erogazione dei sensori viene effettuata ogni tre/sei mesi, allo scopo di monitorare la data di scadenza del materiale stesso, controllare l'effettivo e corretto utilizzo ed effettuare la rivalutazione del paziente. Numero massimo 26 sensori/anno. La fornitura di strisce reattive per la determinazione della glicemia capillare, nei pazienti che utilizzano il FGM, è consentita sino ad un massimo di 50/mese. Richiesta e distribuzione del dispositivo, attualmente, seguiranno le modalità del sistema WebCare, in una prima fase la prescrizione sarà ancora in forma cartacea, successivamente, l’erogazione avverrà attraverso la piattaforma WebDPC.
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APPENDIX 6 List of excluded studies with reasons
Study ID Year Reason for exclusion
Ajjan [1], R. A. 2017 Narrative review
Bailey [2], T 2015 This was a diagnostic accuracy study evaluating the performance and usability of the FreeStyle Libre Flash glucose monitoring system (Abbott Diabetes Care, Alameda, CA) for interstitial glucose results compared with capillary blood glucose results
Bergenstal [3], R. M. 2008 Narrative review
Bonora [4], B 2016 This study was performed to determine the agreement between the factory-calibrated FGM FreeStyle Libre and CGM Dexcom G4 Platinum as well as the . self-monitoring of blood glucose (SMBG) in 8 participants.
Brahimi [5], N 2017 Corresponding letter
Chawla [6], M 2017 The study was performed to assess the glycemic change and to modulate the ongoing antidiabetic therapy for following 3 months. No controls were considered.
Cobry, E[7] 2008 The purpose of this study was to evaluate the effectiveness of directly integrating self-monitoring blood glucose information with insulin pump therapy on overall glycemic control.
Distiller [8], L 2016 In this study the comparison of glycemic and other parameters was between DM1 and DM2 participants
Dover [9], A. R 2017 This study assessed the impact of introducing FGM on HbA1c, hypoglycemia (recorded and self-reported) and quality of life measures. No controls were used.
Edge [10], J 2017 A diagnostic accuracy study: Sensor glucose measurements were compared with capillary blood glucose (BG) measurements on the same participants.
Fokkert [11], M 2017 A diagnostic accuracy study: To evaluate the performance of the FreeStyle Libre Flash continuous glucose monitoring (FSL-CGM) system against established central laboratory methods on the same participants
Gys [12], I 2016 (Conference presentation) A diagnostic accuracy study evaluating FreeStyle® Libre Flash Glucose Monitoring System compared to capillary blood glucose.
Heinemann, L., et al [13] 2015 Commentary
Hermanns, N[14] 2017 Commentary
Maffettone, A[15] 2015 This evaluated the correlation between FGM and capillary blood glucose monitoring in 4 participants with DM2
Olafsdottir, A. F 2017 This study evaluated the correlation between FGM and capillary blood glucose levels between the same participants
Rai [16], S 2016 This study evaluated the correlation between FGM and capillary blood glucose levels between the same participants
Rittmeyer [17], D[17] 2015 This study evaluated the correlation between FGM and capillary blood glucose levels between the same participants
Rivers, S[18] 2006 This study evaluated the accuracy of FGM and another glucose meter (One Touch Ultra)
Sieber, J[19] 2015 A single arm study.
Slattery, D[20] 2017 Narrative review
Thomas [21], L 2008 Accuracy study between FGM,
Weinzimer [22], S. A 2005 This study evaluated the accuracy of FGM and another glucose meter (One Touch Ultra)
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References
1. Ajjan, R.A., How Can We Realize the Clinical Benefits of Continuous Glucose Monitoring? Diabetes
Technol Ther, 2017. 19(S2): p. S27-s36.
2. Bailey, T., et al., The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes and Therapeutics, 2016. 18: p. S18-S19.
3. Bergenstal, R.M., Evaluating the Accuracy of Modern Glucose Meters. Insulin, 2008. 3(1): p. 5-14. 4. Bonora, B., et al., Head-to-head comparison between flash and continuous glucose monitoring
systems in outpatients with type 1 diabetes. J Endocrinol Invest, 2016. 39(12): p. 1391-1399.
5. Brahimi, N., L. Potier, and K. Mohammedi, Cutaneous adverse events related to FreeStyle Libre device. Lancet, 2017. 389(10077): p. 1396.
6. Chawla, M., et al., Leveraging flash glucose monitoring for modulation and assessment of glycemic change in type 1 and type 2 diabetes. Diabetes, 2017. 66: p. A245.
7. Cobry, E., et al. Use of CoZmonitor in youth with type 1 diabetes. Pediatric diabetes, 2008. 9, 148-151 DOI: 10.1111/j.1399-5448.2007.00268.x.
8. Distiller, L., I. Cranston, and R. Mazze First Clinical Experience with Retrospective Flash Glucose Monitoring (FGM) Analysis in South Africa: characterizing Glycemic Control with Ambulatory Glucose Profile. Journal of diabetes science and technology, 2016. 10, 1294-1302 DOI:
10.1177/1932296816648165. 9. Dover, A.R., et al., Flash Glucose Monitoring Improves Outcomes in a Type 1 Diabetes Clinic. J
Diabetes Sci Technol, 2017. 11(2): p. 442-443.
10. Edge, J., et al., An alternative sensor-based method for glucose monitoring in children and young people with diabetes. Arch Dis Child, 2017. 102(6): p. 543-549.
11. Fokkert, M., et al. Performance of the freestyle libre flash glucose monitoring system in patients with type 1 and 2 diabetes mellitus. BMJ open diabetes research and care, 2017. 5, DOI:
10.1136/bmjdrc-2016-000320.
12. Gys, I., et al., Evaluation of the Freestyle Libre Flash glucose monitoring system in children and adolescents with type 1 diabetes. Pediatric Diabetes, 2016. 17: p. 85-86.
13. Heinemann, L. and G. Freckmann, CGM Versus FGM; or, Continuous Glucose Monitoring Is Not Flash Glucose Monitoring. J Diabetes Sci Technol, 2015. 9(5): p. 947-50.
14. Hermanns, N., D. Ehrmann, and B. Kulzer, How Much Accuracy of Interstitial Glucose Measurement Is Enough? Is There a Need for New Evidence? J Diabetes Sci Technol, 2017. 11(2): p. 296-298.
15. Maffettone, A., et al., Self-monitoring and assessment of glycemic variability in patients with T1DM and T2DM using the new system of Flash Glucose Monitoring (Freestyle FLASH, Abbott). Italian Journal of Medicine, 2015. 9: p. 60.
16. Rai, S., A. Hulse, and P. Kumar, Feasibility and acceptability of ambulatory glucose profile in children with Type 1 diabetes mellitus: A pilot study. Indian J Endocrinol Metab, 2016. 20(6): p. 790-794.
17. Rittmeyer, D., et al., A novel glucose monitoring system versus a conventional SMBG system: Time and step analysis. Diabetes Technology and Therapeutics, 2015. 17: p. A88.
18. Rivers, S., et al. Precision and accuracy of two blood glucose meters: freeStyle Flash versus One Touch Ultra. American journal of health-system pharmacy, 2006. 63, 1411-1416 DOI: 10.2146/ajhp050473.
19. Sieber, J., et al., Evaluation of a Methodology for Estimating HbA1c Value by a New Glucose Meter. J Diabetes Sci Technol, 2015. 10(1): p. 67-71.
20. Slattery, D. and P. Choudhary, Clinical Use of Continuous Glucose Monitoring in Adults with Type 1 Diabetes. Diabetes Technol Ther, 2017. 19(S2): p. S55-s61.
21. Thomas, L., et al. A glucose meter accuracy and precision comparison: the FreeStyle Flash Versus the Accu-Chek Advantage, Accu-Chek Compact Plus, Ascensia Contour, and the BD Logic. Diabetes technology & therapeutics, 2008. 10, 102-110 DOI: 10.1089/dia.2007.0244.
22. Weinzimer, S.A., Accuracy of newer-generation home blood glucose meters in a Diabetes Research in Children Network (DirecNet) inpatient exercise study. Diabetes and Therapeutics, 2005. 7(5): p. 675-680.
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APPENDIX 7 – Analisi di impatto finanziario regionale del
dispositivo FSL
Metodo
L’analisi di impatto finanziario è stata effettuata utilizzando le seguenti fonti informative:
Istat, Indagine multiscopo "Aspetti della vita quotidiana" anni 2015-2017;
Istat - Previsioni della popolazione - Anni 2016-2065 (http://dati.istat.it/) – periodo 2018-
2020;
NSIS-Flusso Contratti (accesso gennaio 2018);
Informazioni provenienti dal produttore della tecnologia.
L’indagine multiscopo ISTAT è stata consultata allo scopo di rilevare le prevalenze regionali del
diabete nei tre anni (2015-2018). A partire da tali prevalenze sono state calcolate le stime di
prevalenza del diabete per gli anni 2018-2020 calcolata aggiungendo/sottraendo alla prevalenza di
ciascun anno l’incremento medio annuo di accrescimento, ottenuto come differenza tra la media
geometrica degli indici di incremento annuale e il valore 1 espresso in percentuale.
La previsione della popolazione residente per gli anni 2018-2020 è stata anch’essa rilevata
utilizzando la banca dati ISTAT a cui sono state applicate le stime di prevalenza del diabete. Dai
report a disposizione del Ministero della Salute
(http://www.salute.gov.it/portale/salute/p1_5.jsp?id=170&area=Malattie_endocrine_e_metabolich
e) si calcola che il 90% dei pazienti con diabete è di tipo 2 (e il restante 10% e di tipo 1) e che il
9% di essi è sottoposto a trattamento insulinico intensivo (L’uso dei farmaci in Italia. AIFA
Rapporto Nazionale Anno 2013), mentre il DM1 è sempre insulino intensivo.
Il prezzo dei dispositivi (IVA esclusa) è stato invece reperito mediante consultazione (gennaio
2018) del NSIS-Flusso Contratti e confrontato con le informazioni fornite dal produttore.
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Risultati
La tabella 1 mostra le stime di prevalenza calcolate per gli anni 2018-2020 e, come specificato già
nella sezione dei metodi, sono state calcolate a partire dalla serie storica delle prevalenze del
diabete nella popolazione italiana, riportate nei report ISTAT, sullo stato di salute della popolazione
per gli anni 2015-2017. Come si può notare dalla tabella, le prevalenze variano da regione a
regione sia in termini di percentuale che in termini di aumento o diminuzione. Avremo così delle
regioni con stime di prevalenza nel triennio più elevate delle altre ma che tendono all’aumento
(es. Basilicata) e regioni invece che pur avendo una prevalenza più alta di altre hanno valori
stimati nel triennio in diminuzione (es. Calabria). Le regioni del centro sud hanno una prevalenza
stimata che è rispetto alle regioni del nord più elevata.
Tabella 1: stime di prevalenza diabete anni 2018-2020 (valori %)
Regione 2018 2019 2020
Abruzzo* 6.31 6.87 7.47
Basilicata 8.35 9.17 10.07
Bolzano* 3.68 3.99 4.32
Calabria 7.75 7.61 7.47
Campania 5.26 4.85 4.47
Emilia-Romagna 4.91 4.73 4.55
Friuli-V. Giulia 4.46 4.32 4.18
Lazio 6.45 6.40 6.35
Liguria* 4.86 5.02 5.19
Lombardia 4.80 4.91 5.02
Marche 4.17 3.95 3.74
Molise* 4.63 4.37 4.12
Piemonte 4.15 3.82 3.52
Puglia* 5.56 5.42 5.28
Sardegna* 5.41 5.63 5.86
Sicilia 6.10 6.21 6.31
Toscana 5.06 5.22 5.39
Trento 2.79 2.44 2.13
Umbria 6.67 7.30 7.98
V. d'Aosta* 3.77 3.39 3.05
Veneto 4.35 4.40 4.45
ITALIA 5.25 5.20 5.15
Fonte: Elaborazione Agenas su dati ISTAT - Indagine multiscopo "Aspetti della vita quotidiana" anni 2015-2017.
* Regioni a cui è stato applicato un prezzo medio.
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Applicando tali stime di prevalenze alle stime di popolazione ISTAT per gli anni 2018-20 abbiamo
calcolato le popolazioni DM1 e DM2 insulino dipendenti per regione. I risultati sono riportati nella
tabella 2 e nella tabella 3 per DM1 e DM2 rispettivamente. Le stime di popolazione DM1 e DM2
insulino dipendente rispettano gli andamenti delle stime di prevalenza e pertanto saranno in
aumento o in diminuzione in linea con l’andamento della relativa prevalenza.
Tabella 2: Popolazione e stime di popolazione DM1 (anni 2018-2020)
Regione 2018 2019 2020
Abruzzo* 8.349 9.069 9.850
Basilicata 4.746 5.189 5.672
Calabria 15.205 14.883 14.564
Campania 30.639 28.190 25.931
Emilia-Romagna 21.937 21.162 20.410
Friuli-Venezia Giulia 5.426 5.248 5.076
Lazio 38.213 38.032 37.846
Liguria* 7.590 7.821 8.057
Lombardia 48.294 49.459 50.648
Marche 6.416 6.068 5.739
Molise* 1.438 1.354 1.275
PA Bolzano* 1.944 2.118 2.306
PA Trento 1.514 1.327 1.162
Piemonte 18.228 16.775 15.437
Puglia* 22.531 21.896 21.276
Sardegna* 8.932 9.271 9.621
Sicilia 30.793 31.229 31.673
Toscana 18.982 19.609 20.253
Umbria 5.928 6.473 7.069
Valle d'Aosta* 479 430 386
Veneto 21.384 21.636 21.891
Totale 318.490 315.432 312.367
Fonte: Elaborazione Agenas su dati ISTAT; * Regioni a cui è stato applicato un prezzo medio.
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Tabella 3: Popolazione anno 2017 e stime di popolazione DM2 (anni 2018-2020)
Regioni 2018 2019 2020
Abruzzo* 6.763 7.346 7.979
Basilicata 3.845 4.203 4.594
Calabria 12.316 12.055 11.797
Campania 24.818 22.834 21.004
Emilia-Romagna 17.769 17.141 16.532
Friuli-Venezia Giulia 4.395 4.251 4.112
Lazio 30.953 30.806 30.655
Liguria* 6.148 6.335 6.526
Lombardia 39.118 40.062 41.025
Marche 5.197 4.915 4.649
Molise* 1.165 1.097 1.033
PA Bolzano* 1.575 1.715 1.868
PA Trento 1.227 1.075 942
Piemonte 14.764 13.588 12.504
Puglia* 18.250 17.736 17.234
Sardegna* 7.235 7.510 7.793
Sicilia 24.942 25.296 25.655
Toscana 15.375 15.883 16.405
Umbria 4.802 5.243 5.725
Valle d'Aosta* 388 348 313
Veneto 17.321 17.526 17.731
Totale 257.977 255.500 253.017
Fonte: Elaborazione Agenas su dati ISTAT; * Regioni a cui è stato applicato un prezzo medio.
Per quanto riguarda l’analisi del Flusso Contratti sono stati rilevati i prezzi 2017 (IVA esclusa) dei
sensori e abbiamo rilevato che, in accordo con le indicazioni del produttore, i lettori (quando
imputati nel flusso) sono forniti gratuitamente. Considerando un numero medio di sensori pari a 26
(uno ogni due settimane per 12 mesi) abbiamo calcolato il costo medio per paziente per regione.
Ovviamente a prezzo del sensore più alto corrisponderà un costo annuale per paziente più elevato
(Tabella 4). Per quanto riguarda il lettore e il numero di strisce necessarie alla misurazione del
sangue capillare utilizzando il sistema FSL essi sono forniti gratuitamente dal produttore.
107
Tabella 4: Prezzo sensore (IVA esclusa) e costo medio per paziente (anno 2017)
Regione Prezzo sensore (IVA esclusa) Costo per paziente 2017
Basilicata € 45,00 €1.170
Calabria € 35,00 €910
Campania € 32,75 €851,50
Emilia-Romagna € 49,00 €1.274
Friuli-Venezia Giulia € 49,00 €1.274
Lazio € 35,00 €910
Lombardia € 35,00 €910
Marche € 42,00 €1.092
PA Trento € 36,00 €936
Piemonte € 42,00 €1.092
Sicilia € 32,75 €851,50
Toscana € 35,00 €910
Umbria € 42,00 €1.092
Veneto € 36,00 €936
Fonte: Elaborazione Agenas su dati NSIS-Flusso Contratti (anno 2017).
Utilizzando le stime di popolazione DM1 e DM2 insulino dipendenti; un numero annuo di sensori
pari a 26 (un sensore ogni due settimane per 12 mesi); i prezzi rilevati dal Flusso Contratti e
applicando il valore medio di 37 euro alle regioni per le quali non abbiamo informazioni in merito
all’utilizzo del FSL a livello di servizio sanitario regionale (SSR) abbiamo calcolato le stima di spesa
per il periodo 2018-2020. Le stime di spesa sono state calcolate considerando differenti percentuali
di pazienti DM1 e DM 2 trattate con il sistema FSL. Le tabelle seguenti riportano le percentuali di
popolazione trattata e le relative stime di spesa per regione per tre anni (2018-2020).
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Tabella 5: Stime di popolazione DM1 (anni 2018-2020)
Regione 2018 2019 2020
5% 10% 20% 30% 50% 70% 100% 5% 10% 20% 30% 50% 70% 100% 5% 10% 20% 30% 50% 70% 100%
Abruzzo 417 835 1670 2505 4174 5844 8349 453 907 1814 2721 4534 6348 9069 493 985 1970 2955 4925 6895 9850
Basilicata 237 475 949 1424 2373 3323 4746 259 519 1038 1557 2595 3632 5189 284 567 1134 1702 2836 3970 5672
Calabria 760 1520 3041 4561 7602 10643 15205 744 1488 2977 4465 7442 10418 14883 728 1456 2913 4369 7282 10195 14564
Campania 1532 3064 6128 9192 15320 21448 30639 1410 2819 5638 8457 14095 19733 28190 1297 2593 5186 7779 12965 18151 25931
Emilia-Romagna 1097 2194 4387 6581 10968 15356 21937 1058 2116 4232 6349 10581 14813 21162 1020 2041 4082 6123 10205 14287 20410
Friuli-Venezia Giulia 271 543 1085 1628 2713 3798 5426 262 525 1050 1574 2624 3674 5248 254 508 1015 1523 2538 3553 5076
Lazio 1911 3821 7643 11464 19107 26749 38213 1902 3803 7606 11409 19016 26622 38032 1892 3785 7569 11354 18923 26492 37846
Liguria 379 759 1518 2277 3795 5313 7590 391 782 1564 2346 3910 5474 7821 403 806 1611 2417 4028 5640 8057
Lombardia 2415 4829 9659 14488 24147 33806 48294 2473 4946 9892 14838 24730 34621 49459 2532 5065 10130 15195 25324 35454 50648
Marche 321 642 1283 1925 3208 4491 6416 303 607 1214 1820 3034 4248 6068 287 574 1148 1722 2870 4017 5739
Molise 72 144 288 431 719 1007 1438 68 135 271 406 677 948 1354 64 128 255 383 638 893 1275
PA Bolzano 97 194 389 583 972 1361 1944 106 212 424 635 1059 1482 2118 115 231 461 692 1153 1614 2306
PA Trento 76 151 303 454 757 1060 1514 66 133 265 398 663 929 1327 58 116 232 349 581 814 1162
Piemonte 911 1823 3646 5468 9114 12759 18228 839 1677 3355 5032 8387 11742 16775 772 1544 3087 4631 7718 10806 15437
Puglia 1127 2253 4506 6759 11265 15772 22531 1095 2190 4379 6569 10948 15327 21896 1064 2128 4255 6383 10638 14893 21276
Sardegna 447 893 1786 2680 4466 6253 8932 464 927 1854 2781 4636 6490 9271 481 962 1924 2886 4810 6735 9621
Sicilia 1540 3079 6159 9238 15396 21555 30793 1561 3123 6246 9369 15615 21861 31229 1584 3167 6335 9502 15836 22171 31673
Toscana 949 1898 3796 5695 9491 13287 18982 980 1961 3922 5883 9804 13726 19609 1013 2025 4051 6076 10126 14177 20253
Umbria 296 593 1186 1778 2964 4150 5928 324 647 1295 1942 3237 4531 6473 353 707 1414 2121 3534 4948 7069
Valle d'Aosta 24 48 96 144 240 336 479 22 43 86 129 215 301 430 19 39 77 116 193 270 386
Veneto 1069 2138 4277 6415 10692 14969 21384 1082 2164 4327 6491 10818 15146 21636 1095 2189 4378 6567 10945 15323 21891
Fonte: Elaborazione Agenas
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Tabella 6: Stime di spesa FSL per DM1 per percentuali di pazienti trattati
Regione % Pazienti trattati 2018 2019 2020
Abruzzo* 5% € 401.577 € 436.217 € 473.807
€ 37,00 10% € 803.155 € 872.433 € 947.615
20% € 1.606.309 € 1.744.866 € 1.895.230
30% € 2.409.464 € 2.617.300 € 2.842.844
50% € 4.015.774 € 4.362.166 € 4.738.074
70% € 5.622.083 € 6.107.033 € 6.633.304
100% € 8.031.547 € 8.724.332 € 9.476.148
Basilicata 5% € 277.668 € 303.560 € 331.810
€ 45,00 10% € 555.336 € 607.120 € 663.620
20% € 1.110.672 € 1.214.239 € 1.327.240
30% € 1.666.008 € 1.821.359 € 1.990.860
50% € 2.776.680 € 3.035.599 € 3.318.100
70% € 3.887.352 € 4.249.838 € 4.645.340
100% € 5.553.360 € 6.071.197 € 6.636.200
Calabria 5% € 691.813 € 677.179 € 662.683
€ 35,00 10% € 1.383.626 € 1.354.358 € 1.325.366
20% € 2.767.253 € 2.708.715 € 2.650.732
30% € 4.150.879 € 4.063.073 € 3.976.098
50% € 6.918.132 € 6.771.788 € 6.626.831
70% € 9.685.384 € 9.480.503 € 9.277.563
100% € 13.836.263 € 13.543.575 € 13.253.661
Campania 5% € 1.304.471 € 1.200.209 € 1.103.996
€ 32,75 10% € 2.608.942 € 2.400.417 € 2.207.992
20% € 5.217.885 € 4.800.834 € 4.415.984
30% € 7.826.827 € 7.201.251 € 6.623.976
50% € 13.044.711 € 12.002.085 € 11.039.960
70% € 18.262.596 € 16.802.919 € 15.455.944
100% € 26.089.423 € 24.004.171 € 22.079.920
Emilia-Romagna 5% € 1.397.383 € 1.348.007 € 1.300.112
€ 49,00 10% € 2.794.765 € 2.696.015 € 2.600.223
20% € 5.589.530 € 5.392.030 € 5.200.447
30% € 8.384.295 € 8.088.044 € 7.800.670
50% € 13.973.825 € 13.480.074 € 13.001.117
70% € 19.563.355 € 18.872.104 € 18.201.564
100% € 27.947.650 € 26.960.148 € 26.002.235
Friuli-Venezia Giulia 5% € 345.622 € 334.313 € 323.346
€ 49,00 10% € 691.244 € 668.625 € 646.691
20% € 1.382.488 € 1.337.251 € 1.293.382
30% € 2.073.732 € 2.005.876 € 1.940.073
50% € 3.456.221 € 3.343.127 € 3.233.456
70% € 4.838.709 € 4.680.378 € 4.526.838
100% € 6.912.441 € 6.686.254 € 6.466.912
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Regione % Pazienti trattati 2018 2019 2020
Lazio 5% € 1.738.702 € 1.730.433 € 1.722.002
€ 35,00 10% € 3.477.404 € 3.460.867 € 3.444.004
20% € 6.954.807 € 6.921.734 € 6.888.007
30% € 10.432.211 € 10.382.601 € 10.332.011
50% € 17.387.018 € 17.304.334 € 17.220.018
70% € 24.341.825 € 24.226.068 € 24.108.025
100% € 34.774.036 € 34.608.669 € 34.440.036
Liguria* 5% € 365.079 € 376.176 € 387.535
€ 37,00 10% € 730.157 € 752.353 € 775.070
20% € 1.460.314 € 1.504.705 € 1.550.141
30% € 2.190.472 € 2.257.058 € 2.325.211
50% € 3.650.786 € 3.761.763 € 3.875.352
70% € 5.111.100 € 5.266.468 € 5.425.492
100% € 7.301.572 € 7.523.526 € 7.750.703
Lombardia 5% € 2.197.390 € 2.250.395 € 2.304.504
€ 35,00 10% € 4.394.779 € 4.500.790 € 4.609.009
20% € 8.789.558 € 9.001.579 € 9.218.017
30% € 13.184.337 € 13.502.369 € 13.827.026
50% € 21.973.895 € 22.503.948 € 23.045.044
70% € 30.763.453 € 31.505.527 € 32.263.061
100% € 43.947.790 € 45.007.895 € 46.090.087
Marche 5% € 350.308 € 331.326 € 313.357
€ 42,00 10% € 700.616 € 662.652 € 626.715
20% € 1.401.232 € 1.325.303 € 1.253.429
30% € 2.101.848 € 1.987.955 € 1.880.144
50% € 3.503.081 € 3.313.258 € 3.133.573
70% € 4.904.313 € 4.638.561 € 4.387.002
100% € 7.006.162 € 6.626.516 € 6.267.146
Molise* 5% € 69.169 € 65.140 € 61.329
€ 37,00 10% € 138.337 € 130.280 € 122.659
20% € 276.675 € 260.560 € 245.318
30% € 415.012 € 390.839 € 367.977
50% € 691.687 € 651.399 € 613.295
70% € 968.361 € 911.959 € 858.612
100% € 1.383.373 € 1.302.798 € 1.226.589
PA Bolzano* 5% € 93.504 € 101.855 € 110.918
€ 37,00 10% € 187.007 € 203.710 € 221.836
20% € 374.014 € 407.421 € 443.673
30% € 561.021 € 611.131 € 665.509
50% € 935.035 € 1.018.552 € 1.109.182
70% € 1.309.049 € 1.425.973 € 1.552.855
100% € 1.870.071 € 2.037.105 € 2.218.364
111
Regione % Pazienti trattati 2018 2019 2020
PA Trento 5% € 70.876 € 62.095 € 54.405
€ 36,00 10% € 141.752 € 124.190 € 108.810
20% € 283.504 € 248.381 € 217.620
30% € 425.256 € 372.571 € 326.430
50% € 708.760 € 620.952 € 544.049
70% € 992.264 € 869.333 € 761.669
100% € 1.417.520 € 1.241.905 € 1.088.099
Piemonte 5% € 995.237 € 915.908 € 842.840
€ 42,00 10% € 1.990.473 € 1.831.815 € 1.685.680
20% € 3.980.946 € 3.663.630 € 3.371.359
30% € 5.971.419 € 5.495.445 € 5.057.039
50% € 9.952.366 € 9.159.075 € 8.428.398
70% € 13.933.312 € 12.822.705 € 11.799.758
100% € 19.904.731 € 18.318.151 € 16.856.797
Puglia* 5% € 1.083.729 € 1.053.203 € 1.023.396
€ 37,00 10% € 2.167.459 € 2.106.406 € 2.046.791
20% € 4.334.918 € 4.212.813 € 4.093.583
30% € 6.502.377 € 6.319.219 € 6.140.374
50% € 10.837.295 € 10.532.032 € 10.233.956
70% € 15.172.213 € 14.744.844 € 14.327.539
100% € 21.674.590 € 21.064.063 € 20.467.913
Sardegna* 5% € 429.639 € 445.953 € 462.770
€ 37,00 10% € 859.277 € 891.906 € 925.540
20% € 1.718.555 € 1.783.812 € 1.851.080
30% € 2.577.832 € 2.675.718 € 2.776.620
50% € 4.296.387 € 4.459.531 € 4.627.700
70% € 6.014.942 € 6.243.343 € 6.478.780
100% € 8.592.775 € 8.919.062 € 9.255.401
Sicilia 5% € 1.310.996 € 1.329.588 € 1.348.463
€ 32,75 10% € 2.621.992 € 2.659.176 € 2.696.925
20% € 5.243.984 € 5.318.353 € 5.393.850
30% € 7.865.976 € 7.977.529 € 8.090.775
50% € 13.109.960 € 13.295.882 € 13.484.625
70% € 18.353.944 € 18.614.235 € 18.878.475
100% € 26.219.919 € 26.591.764 € 26.969.250
Toscana 5% € 863.684 € 892.197 € 921.504
€ 35,00 10% € 1.727.369 € 1.784.394 € 1.843.009
20% € 3.454.737 € 3.568.787 € 3.686.017
30% € 5.182.106 € 5.353.181 € 5.529.026
50% € 8.636.843 € 8.921.968 € 9.215.043
70% € 12.091.581 € 12.490.756 € 12.901.060
100% € 17.273.686 € 17.843.937 € 18.430.086
112
Regione % Pazienti trattati 2018 2019 2020
Umbria 5% € 323.683 € 353.450 € 385.941
€ 42,00 10% € 647.367 € 706.900 € 771.882
20% € 1.294.733 € 1.413.801 € 1.543.763
30% € 1.942.100 € 2.120.701 € 2.315.645
50% € 3.236.833 € 3.534.501 € 3.859.408
70% € 4.531.567 € 4.948.302 € 5.403.171
100% € 6.473.667 € 7.069.003 € 7.718.816
Valle d'Aosta* 5% € 23.054 € 20.688 € 18.565
€ 37,00 10% € 46.108 € 41.377 € 37.130
20% € 92.216 € 82.753 € 74.259
30% € 138.324 € 124.130 € 111.389
50% € 230.540 € 206.883 € 185.648
70% € 322.756 € 289.637 € 259.907
100% € 461.080 € 413.766 € 371.296
Veneto 5% € 1.000.753 € 1.012.586 € 1.024.476
€ 36,00 10% € 2.001.506 € 2.025.172 € 2.048.952
20% € 4.003.011 € 4.050.343 € 4.097.905
30% € 6.004.517 € 6.075.515 € 6.146.857
50% € 10.007.528 € 10.125.858 € 10.244.762
70% € 14.010.540 € 14.176.201 € 14.342.667
100% € 20.015.057 € 20.251.715 € 20.489.525
Fonte: Elaborazione Agenas; * Regioni a cui è stato applicato un prezzo medio.
113
Tabella 7: Stime di popolazione DM2 (anni 2018-2020)
Regione 2018 2019 2020
5% 10% 20% 30% 50% 70% 100% 5% 10% 20% 30% 50% 70% 100% 5% 10% 20% 30% 50% 70% 100%
Abruzzo 338 676 1353 2029 3381 4734 6763 367 735 1469 2204 3673 5142 7346 399 798 1596 2394 3989 5585 7979
Basilicata 192 384 769 1153 1922 2691 3845 210 420 841 1261 2102 2942 4203 230 459 919 1378 2297 3216 4594
Calabria 616 1232 2463 3695 6158 8621 12316 603 1206 2411 3617 6028 8439 12055 590 1180 2359 3539 5899 8258 11797
Campania 1241 2482 4964 7445 12409 17373 24818 1142 2283 4567 6850 11417 15984 22834 1050 2100 4201 6301 10502 14703 21004
Emilia-Romagna 888 1777 3554 5331 8884 12438 17769 857 1714 3428 5142 8571 11999 17141 827 1653 3306 4960 8266 11572 16532
Friuli-Venezia Giulia 220 439 879 1318 2197 3076 4395 213 425 850 1275 2126 2976 4251 206 411 822 1233 2056 2878 4112
Lazio 1548 3095 6191 9286 15476 21667 30953 1540 3081 6161 9242 15403 21564 30806 1533 3066 6131 9197 15328 21459 30655
Liguria 307 615 1230 1844 3074 4304 6148 317 633 1267 1900 3167 4434 6335 326 653 1305 1958 3263 4568 6526
Lombardia 1956 3912 7824 11736 19559 27383 39118 2003 4006 8012 12019 20031 28043 40062 2051 4103 8205 12308 20513 28718 41025
Marche 260 520 1039 1559 2598 3638 5197 246 492 983 1475 2458 3441 4915 232 465 930 1395 2324 3254 4649
Molise 58 116 233 349 582 815 1165 55 110 219 329 548 768 1097 52 103 207 310 516 723 1033
PA Bolzano 79 157 315 472 787 1102 1575 86 172 343 515 858 1201 1715 93 187 374 560 934 1307 1868
PA Trento 61 123 245 368 613 859 1227 54 107 215 322 537 752 1075 47 94 188 282 471 659 942
Piemonte 738 1476 2953 4429 7382 10335 14764 679 1359 2718 4076 6794 9511 13588 625 1250 2501 3751 6252 8753 12504
Puglia 912 1825 3650 5475 9125 12775 18250 887 1774 3547 5321 8868 12415 17736 862 1723 3447 5170 8617 12064 17234
Sardegna 362 724 1447 2171 3618 5065 7235 375 751 1502 2253 3755 5257 7510 390 779 1559 2338 3897 5455 7793
Sicilia 1247 2494 4988 7483 12471 17459 24942 1265 2530 5059 7589 12648 17707 25296 1283 2565 5131 7696 12827 17958 25655
Toscana 769 1538 3075 4613 7688 10763 15375 794 1588 3177 4765 7942 11118 15883 820 1640 3281 4921 8202 11483 16405
Umbria 240 480 960 1441 2401 3361 4802 262 524 1049 1573 2622 3670 5243 286 573 1145 1718 2863 4008 5725
Valle d'Aosta 19 39 78 116 194 272 388 17 35 70 105 174 244 348 16 31 63 94 156 219 313
Veneto 866 1732 3464 5196 8660 12125 17321 876 1753 3505 5258 8763 12268 17526 887 1773 3546 5319 8866 12412 17731
Fonte: Elaborazione Agenas
114
Tabella 8: Stime di spesa FSL per DM2 per percentuali di pazienti trattati
Regione % pazienti trattati 2018 2019 2020
Abruzzo* 5% € 325.278 € 353.335 € 383.784
€ 37,00 10% € 650.555 € 706.671 € 767.568
20% € 1.301.111 € 1.413.342 € 1.535.136
30% € 1.951.666 € 2.120.013 € 2.302.704
50% € 3.252.777 € 3.533.355 € 3.837.840
70% € 4.553.887 € 4.946.697 € 5.372.976
100% € 6.505.553 € 7.066.709 € 7.675.680
Basilicata 5% € 224.911 € 245.883 € 268.766
€ 45,00 10% € 449.822 € 491.767 € 537.532
20% € 899.644 € 983.534 € 1.075.064
30% € 1.349.466 € 1.475.301 € 1.612.597
50% € 2.249.111 € 2.458.835 € 2.687.661
70% € 3.148.755 € 3.442.369 € 3.762.725
100% € 4.498.221 € 4.917.670 € 5.375.322
Calabria 5% € 560.369 € 548.515 € 536.773
€ 35,00 10% € 1.120.737 € 1.097.030 € 1.073.547
20% € 2.241.475 € 2.194.059 € 2.147.093
30% € 3.362.212 € 3.291.089 € 3.220.640
50% € 5.603.687 € 5.485.148 € 5.367.733
70% € 7.845.161 € 7.679.207 € 7.514.826
100% € 11.207.373 € 10.970.296 € 10.735.466
Campania 5% € 1.056.622 € 972.169 € 894.237
€ 32,75 10% € 2.113.243 € 1.944.338 € 1.788.474
20% € 4.226.487 € 3.888.676 € 3.576.947
30% € 6.339.730 € 5.833.013 € 5.365.421
50% € 10.566.216 € 9.721.689 € 8.942.368
70% € 14.792.703 € 13.610.365 € 12.519.315
100% € 21.132.433 € 19.443.378 € 17.884.735
Emilia-Romagna 5% € 1.131.880 € 1.091.886 € 1.053.090
€ 49,00 10% € 2.263.760 € 2.183.772 € 2.106.181
20% € 4.527.519 € 4.367.544 € 4.212.362
30% € 6.791.279 € 6.551.316 € 6.318.543
50% € 11.318.798 € 10.918.860 € 10.530.905
70% € 15.846.318 € 15.286.404 € 14.743.267
100% € 22.637.597 € 21.837.720 € 21.061.810
Friuli-Venezia Giulia 5% € 279.954 € 270.793 € 261.910
€ 49,00 10% € 559.908 € 541.587 € 523.820
20% € 1.119.815 € 1.083.173 € 1.047.640
30% € 1.679.723 € 1.624.760 € 1.571.459
50% € 2.799.539 € 2.707.933 € 2.619.099
70% € 3.919.354 € 3.791.106 € 3.666.739
100% € 5.599.077 € 5.415.866 € 5.238.198
115
Regione % pazienti trattati 2018 2019 2020
Lazio 5% € 1.408.348 € 1.401.651 € 1.394.821
€ 35,00 10% € 2.816.697 € 2.803.302 € 2.789.643
20% € 5.633.394 € 5.606.604 € 5.579.286
30% € 8.450.091 € 8.409.906 € 8.368.929
50% € 14.083.484 € 14.016.511 € 13.948.215
70% € 19.716.878 € 19.623.115 € 19.527.501
100% € 28.166.969 € 28.033.022 € 27.896.429
Liguria* 5% € 295.714 € 304.703 € 313.903
€ 37,00 10% € 591.427 € 609.406 € 627.807
20% € 1.182.855 € 1.218.811 € 1.255.614
30% € 1.774.282 € 1.828.217 € 1.883.421
50% € 2.957.137 € 3.047.028 € 3.139.035
70% € 4.139.991 € 4.265.839 € 4.394.649
100% € 5.914.273 € 6.094.056 € 6.278.070
Lombardia 5% € 1.779.886 € 1.822.820 € 1.866.649
€ 35,00 10% € 3.559.771 € 3.645.639 € 3.733.297
20% € 7.119.542 € 7.291.279 € 7.466.594
30% € 10.679.313 € 10.936.918 € 11.199.891
50% € 17.798.855 € 18.228.197 € 18.666.485
70% € 24.918.397 € 25.519.476 € 26.133.080
100% € 35.597.710 € 36.456.395 € 37.332.971
Marche 5% € 283.750 € 268.374 € 253.819
€ 42,00 10% € 567.499 € 536.748 € 507.639
20% € 1.134.998 € 1.073.496 € 1.015.278
30% € 1.702.497 € 1.610.243 € 1.522.916
50% € 2.837.495 € 2.683.739 € 2.538.194
70% € 3.972.494 € 3.757.234 € 3.553.472
100% € 5.674.991 € 5.367.478 € 5.076.388
Molise* 5% € 56.027 € 52.763 € 49.677
€ 37,00 10% € 112.053 € 105.527 € 99.354
20% € 224.106 € 211.053 € 198.707
30% € 336.160 € 316.580 € 298.061
50% € 560.266 € 527.633 € 496.769
70% € 784.372 € 738.687 € 695.476
100% € 1.120.532 € 1.055.267 € 993.537
PA Bolzano* 5% € 75.738 € 82.503 € 89.844
€ 37,00 10% € 151.476 € 165.006 € 179.688
20% € 302.951 € 330.011 € 359.375
30% € 454.427 € 495.017 € 539.063
50% € 757.379 € 825.028 € 898.438
70% € 1.060.330 € 1.155.039 € 1.257.813
100% € 1.514.757 € 1.650.055 € 1.796.875
116
Regione % pazienti trattati 2018 2019 2020
PA Trento 5% € 57.410 € 50.297 € 44.068
€ 36,00 10% € 114.819 € 100.594 € 88.136
20% € 229.638 € 201.189 € 176.272
30% € 344.457 € 301.783 € 264.408
50% € 574.096 € 502.971 € 440.680
70% € 803.734 € 704.160 € 616.952
100% € 1.148.191 € 1.005.943 € 881.360
Piemonte 5% € 806.142 € 741.885 € 682.700
€ 42,00 10% € 1.612.283 € 1.483.770 € 1.365.401
20% € 3.224.566 € 2.967.540 € 2.730.801
30% € 4.836.850 € 4.451.311 € 4.096.202
50% € 8.061.416 € 7.418.851 € 6.827.003
70% € 11.285.983 € 10.386.391 € 9.557.804
100% € 16.122.832 € 14.837.702 € 13.654.005
Puglia* 5% € 877.821 € 853.095 € 828.950
€ 37,00 10% € 1.755.642 € 1.706.189 € 1.657.901
20% € 3.511.284 € 3.412.378 € 3.315.802
30% € 5.266.925 € 5.118.567 € 4.973.703
50% € 8.778.209 € 8.530.946 € 8.289.505
70% € 12.289.492 € 11.943.324 € 11.605.307
100% € 17.556.418 € 17.061.891 € 16.579.009
Sardegna* 5% € 348.007 € 361.222 € 374.844
€ 37,00 10% € 696.015 € 722.444 € 749.687
20% € 1.392.029 € 1.444.888 € 1.499.375
30% € 2.088.044 € 2.167.332 € 2.249.062
50% € 3.480.074 € 3.612.220 € 3.748.437
70% € 4.872.103 € 5.057.108 € 5.247.812
100% € 6.960.147 € 7.224.440 € 7.496.874
Sicilia 5% € 1.061.907 € 1.076.966 € 1.092.255
€ 32,75 10% € 2.123.813 € 2.153.933 € 2.184.509
20% € 4.247.627 € 4.307.866 € 4.369.019
30% € 6.371.440 € 6.461.799 € 6.553.528
50% € 10.619.067 € 10.769.664 € 10.922.546
70% € 14.866.694 € 15.077.530 € 15.291.565
100% € 21.238.135 € 21.539.329 € 21.845.093
Toscana 5% € 699.584 € 722.679 € 746.418
€ 35,00 10% € 1.399.169 € 1.445.359 € 1.492.837
20% € 2.798.337 € 2.890.718 € 2.985.674
30% € 4.197.506 € 4.336.077 € 4.478.511
50% € 6.995.843 € 7.226.794 € 7.464.185
70% € 9.794.180 € 10.117.512 € 10.449.859
100% € 13.991.686 € 14.453.589 € 14.928.370
117
Regione % pazienti trattati 2018 2019 2020
Umbria 5% € 262.184 € 286.295 € 312.612
€ 42,00 10% € 524.367 € 572.589 € 625.224
20% € 1.048.734 € 1.145.178 € 1.250.448
30% € 1.573.101 € 1.717.768 € 1.875.672
50% € 2.621.835 € 2.862.946 € 3.126.120
70% € 3.670.569 € 4.008.124 € 4.376.569
100% € 5.243.670 € 5.725.892 € 6.252.241
Valle d'Aosta* 5% € 18.674 € 16.758 € 15.037
€ 37,00 10% € 37.347 € 33.515 € 30.075
20% € 74.695 € 67.030 € 60.150
30% € 112.042 € 100.545 € 90.225
50% € 186.737 € 167.575 € 150.375
70% € 261.432 € 234.606 € 210.525
100% € 373.474 € 335.151 € 300.750
Veneto 5% € 810.610 € 820.194 € 829.826
€ 36,00 10% € 1.621.220 € 1.640.389 € 1.659.652
20% € 3.242.439 € 3.280.778 € 3.319.303
30% € 4.863.659 € 4.921.167 € 4.978.955
50% € 8.106.098 € 8.201.945 € 8.298.258
70% € 11.348.537 € 11.482.722 € 11.617.561
100% € 16.212.196 € 16.403.889 € 16.596.515
Fonte: Elaborazione Agenas; * Regioni a cui è stato applicato un prezzo medio.
118
APPENDIX 8 - List of patients associations responding to
the public call and pointed out by experts
Associazioni di pazienti rispondenti alla Call pubblica Agenas
Associazione Nazionale Italiana Atleti Diabetici
Associazione Gida affiliata FAND
Federazione Diabete Sicilia
Diabete Forum
Diabete Italia
Federdiabete.emr.it
Cittadinanzattiva
Coordinamento delle Associazioni pediatriche
Federazione Nazionale diabete Giovanile
Associazione Italiana Diabetici
Associazione Diabetici della Provincia di Milano
CLAD Coordinamento Lombardia Ass Dia
119
APPENDIX 9 - Template to collect Patients Associations’
views
Guida alla compilazione
Nella sezione introduttiva della scheda si chiede di fornire alcune informazioni generali sul Compilatore e sull’Associazione Pazienti che
rappresenta.
Nelle sezioni successive viene richiesta una descrizione relativa all’esperienza dei pazienti (e care giver dove rilevante) nell’utilizzo delle
tecnologie elencate, ai benefici e aspetti negativi delle stesse e all’esistenza di gruppi di pazienti che potrebbero avere punti di vista
particolari o bisogni specifici.
Cosa intendiamo per paziente e care giver?
Per paziente si intende chiunque viva o abbia vissuto con la malattia per la quale vi è un’indicazione all’uso delle tecnologie in analisi.
Per care giver si intende chiunque assista il paziente su base informale e non retribuita - come ad es. un familiare o un amico. Non
sono dunque inclusi in questa categoria i medici, gli infermieri o altri operatori che siano pagati per fornire cura e assistenza.
Quali sono le informazioni che ci aiutano di più?
Vi saremmo grati se poteste fornire una visione accurata e bilanciata di tutto l’arco di punti di vista di pazienti (e care giver se possibile
e pertinente) sulle tecnologie in analisi.
Le fonti delle informazioni fornite
E’ importante che vengano esplicitate e riportate, per ogni risposta, le fonti delle informazioni fornite e i metodi con cui sono state
raccolte. Per ogni domanda troverete un box in cui viene richiesto di specificare le modalità di raccolta delle informazioni, indicando
una delle modalità proposte.
□ Nella prima modalità l’informazione è fornita direttamente dal compilatore responsabile per l’associazione pazienti di
riferimento, sulla base della sua esperienza e delle conoscenze ottenute nel tempo tramite helpline, contatti vari con gli
iscritti, gruppi di pazienti etc. In questo caso è utile allegare una lista di riferimenti bibliografici o reportistica interna.
□ La seconda modalità è una indagine condotta ad hoc, per es. può essere realizzata inviando/sottoponendo ai pazienti con le
caratteristiche della popolazione di riferimento (in questo caso: persone con DMT1 o DMT2 in terapia insulinica, 3-4 pazienti
per modalità di intervento) il questionario, affinché rispondano alle singole domande personalmente o tramite vostra
intervista.
Conflitto di interessi e pubblicazione
Il compilatore/referente deve firmare un modulo sul conflitto di interessi che vi sarà inviato a parte.
Nel questionario si richiedono informazioni sul finanziamento dell’associazione e sulla sua diffusione territoriale: tali dati contribuiscono a
conferire robustezza alla rilevazione nei confronti di terze parti.
Si chiede inoltre l’assenso alla eventuale pubblicazione in forma sintetica e anonima delle informazioni riportate nel questionario.
120
SI / NO
QUESTIONARIO ASSOCIAZIONI PAZIENTI
INFORMAZIONI SU COMPILATORE
Nome del compilatore:________________________________
Ruolo nell’organizzazione: ________________________________
Email: ________________________________
Telefono: ________________________________
DESCRIZIONE DELL’ASSOCIAZIONE PAZIENTI
Scopo/finalità, funzioni e attività: __________________________________________
Numero iscritti: __________________________________________
Condizioni di salute rappresentate: __________________________________________
Quali sono i servizi forniti e chi li utilizza: _________________________________________
L’Associazione si avvale di consulenti medici e scientifici?
__________________________________________
Fonti di finanziamento ________________________________________ Raggio di azione territoriale dell’associazione:
Internazionale Nazionale Regionale Locale Altro Specificare:
121
1. PUÒ ELENCARE I PRO E CONTRO, DAL PUNTO DI VISTA DEL PAZIENTE INSULINO-DIPENDENTE, DELLE MODALITÀ
DI AUTO-MISURAZIONE DELLE GLICEMIA IN CONTESTO DOMICILIARE DI SEGUITO ELENCATE ? SPECIFICARE SE CI SI
RIFERISCE A PAZIENTI ADULTI O IN ETÀ COMPRESA TRA I 4 E I 17 ANNI Fonti (indicare con una crocetta una solo delle opzioni)
Informazioni fornite dal compilatore sulla base della sua esperienza e/o delle conoscenze ottenute nel tempo tramite helpline, contatti vari con gli iscritti, gruppi di pazienti etc
Indagine condotte tra gli iscritti per la compilazione di questo questionario
Flash CGM (FreeStyle Libre)
Principali benefici e aspetti positivi (pro)
1.____________________
2.____________________
3._____________________
4.____________________
5.____________________
6._____________________
7.____________________
8.____________________
9._____________________
10.______________________
Principali difficoltà e aspetti negativi (contro)
1.____________________
2.____________________
122
3._____________________
4.____________________
5.____________________
6._____________________
7.____________________
8.____________________
9._____________________
10.______________________
Real Time CGM
Principali benefici e aspetti positivi (pro)
1.____________________
2.____________________
3._____________________
4.____________________
5.____________________
6._____________________
7.____________________
8.____________________
123
9._____________________
10.______________________
Principali difficoltà e aspetti negativi (contro)
1.____________________
2.____________________
3._____________________
4.____________________
5.____________________
6._____________________
7.____________________
8.____________________
9._____________________
10.______________________
AUTOCONTROLLO GLICEMICO CON PUNGIDITO E STRISCE REATTIVE
Principali benefici e aspetti positivi (pro)
1.____________________
2.____________________
3._____________________
4.____________________
5.____________________
124
6._____________________
7.____________________
8.____________________
9._____________________
10.______________________
Principali difficoltà e aspetti negativi (contro)
1.____________________
2.____________________
3._____________________
4.____________________
5.____________________
6._____________________
7.____________________
8.____________________
9._____________________
10.______________________
2. CI SONO GRUPPI DI PAZIENTI CHE ABBIANO SPECIFICHE ESIGENZE O PRESENTINO PROBLEMATICHE SPECIFICHE
NELLA GESTIONE DELLA DIVERSE MODALITÀ DI AUTO-MISURAZIONE DELLE GLICEMIA IN CONTESTO
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DOMICILIARE? Per esempio: adolescenti, bambini, anziani, particolari professioni, stili di vita, gruppi etnici, religiosi etc. DM1 o DM2 etc.
Fonti (indicare con una crocetta una solo delle opzioni)
ottenute nel tempo tramite helpline, contatti vari con gli iscritti, gruppi di pazienti etc
Flash –CGM (FREESTYLE LIBRE)
RT-CGM
auto-misurazione glicemica con pungidito e strisce reattive
126
ADDENDUM
We acknowledge receiving the requested data from the Authors of one of the trial [Bolinder 2016]
(doi: 10.1016/S0140-6736(16)31535-5).
The available data show that at 6 months follow-up 7 subjects in the intervention group and 21 in
the control group reported in the their diary symptomatic hypoglycemia (defined as confusion,
visual disturbances, seizures, sweating, or hunger in a person with a glucose level < 3.9 mmol/L).
The difference was statistically significant in favor of F-CGM.
No evidence of difference were observed in the remaining outcomes: severe hypoglycaemia
(requiring third-party assistance), any hypoglycemia, ≥ 5 hypoglycemic symptomatic episodes per
week, number of subjects with poorly controlled diabetes (defined as HbA1c greater than 7.5 or
8.0%) at 3 and 6 months.
Details are reported below.
We received no data from the second trial included in our review (Haak 2017)
Endpoint Source Intervention
arm
Control
arm
P-value
Number of subjects with symptomatic
hypoglycaemia (defined as
confusion, visual disturbances,
seizures, sweating, or hunger in a
person with a glucose level < 3.9
mmol/L) in each group, at 6 months
follow-up.
Diary – 2 week
final phase
7/98 21/93 0.0036
Number of subjects with severe
hypoglycaemia (requiring third-party
assistance) in each group, at 6
months follow-up.
AE CRF – 6
month
treatment
phase
2/119 3/120 1.0000
Number of subjects with hypoglycaemia
(< 3.9 mmol/L ) in each group, at 6
months follow-up.
Sensor derived 117/119ǂ 117/120ǂ 1.0000ǂ
Number of subjects with ≥ 5
hypoglycaemic symptomatic
episodes (see above for definition)
per week in each group, at 6 months
Diary – 2 week
final phase
3/98 1/93 0.6215
127
follow-up.
Number of hypoglycaemic events
(symptomatic and asymptomatic) in
each group, at 6 months follow-up
Symptomatic –
diary
Asymptomatic –
sensor
derived
0.33
1.32
0.47
1.69
0.0063
<0.0001
Number of subjects with poorly
controlled diabetes (defined as
HbA1c greater than 7.5 or 8.0%) at 3
and 6 months follow-up.
CRF
3 month HbA1c
>7.5%
6 month HbA1c >
7.5%
3 month HbA1c
>8.0%
6 month HbA1c >
8.0%
15/119
17/119
3/119
6/119
23/120
27/120
6/120
5/120
0.2155
0.1326
0.4994
0.7686
ǂ Note that this includes participants with as little as 1 hypo event (<3.9 mmol/L) of 60 minutes duration in 16
days (nominal 2 week final phase). We would like to propose an alternative approach:
The number of subjects experiencing greater than 1 hour per day (<3.9 mmol/L) was 81/119 (Intervention) vs
102/120 (control) [p=0.0022].
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Glossary
AGP: Ambulatory Glucose Profile
BD/RDM: Banca Dati e Repertorio Dispositivi Medici – Italian National Medical Devices Inventory
and Database
CE: Conformité Européene – European Conformity
CGM: Continuous Glucose Monitoring
FGM: Flash Continuous Glucose Monitoring
FDA: Food and Drugs Administration
IFU: Instructions for Use
NFC: Near Field Communication
RT-CGM: Real-Time Continuous Glucose Monitoring
SMBG: Self-Monitoring of Blood Glucose
