Description of the technology

Advice Note 2017/ 001 What is the clinical effectiveness, safety and budget impact of the Freestyle Libre System compared with current glucose monitoring methods for people aged 4 years and over with diabetes mellitus who use multiple daily injections of insulin? Freestyle Libre This advice has been produced following completion of an evidence review by the Health Technology Assessment Group (HTAG), in response to a request from the Primary Care Reimbursement Service of the Health Service Executive. Background In February 2017, Abbott Diabetes Care submitted an application to the Primary Care Reimbursement Service (PCRS) of the Health Service Executive for the reimbursement of the FreeStyle Libre flash glucose monitoring system in Ireland. The Health Technology Assessment Group (HTAG) carried out an appraisal of the evidence submitted with this application, in response to a request from the PCRS. Diabetes places a substantial burden on the individual, society and the economy. Much of this burden is attributable to short-term and long-term complications. As the prevalence of diabetes rises, diabetes-related complications represent a growing global public health and health service challenge. Glucose monitoring allows people to self-manage diabetes by making adjustments to their diet, lifestyle and treatment to reduce the risk of diabetes-related complications. Current glucose monitoring methods include self-monitoring blood glucose (SMBG) (finger-prick blood glucose monitoring using testing strips and electronic glucose meters) as well as continuous glucose monitoring (CGM). Current NICE guidelines recommend that people with type 1 diabetes carry out 4-10 tests per day. The Irish College of General Practitioners recommends that people with type 2 diabetes carry out up to 4 tests per day and more often if driving, doing physical activities, experiencing hypoglycaemia, during illness, feeling stressed or consuming alcohol. Evidence has shown that increased frequency of SMBG leads to improvements in glycaemic control, as assessed by HbA1c. However, poor adherence to the recommended frequency of SMBG has been reported as an issue. Description of the technology The Freestyle Libre flash glucose monitoring system is intended to be used as an alternative to current glucose monitoring methods for people who administer multiple daily injections of insulin. The system has two components: a disposable sensor and a reader. Once inserted, the sensor measures glucose levels in interstitial fluid. At each scan, the reader displays current glucose 1 P a g e

levels, levels over the previous 8 hours, and whether glucose levels are trending upwards or downwards (and how fast). 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. In contrast to SMBG, this innovative technology allows glucose readings to be taken noninvasively and unlike CGM the Freestyle Libre sensor does not need to be calibrated with a blood sample. However, SMBG is still required during periods of rapidly changing glucose levels, or if hypoglycaemia or impending hypoglycaemia is reported, or the symptoms do not match the system readings. Also drivers will need to continue with SMBG before driving (and every 2 hours thereafter if on a long drive) to meet current driving requirements in Ireland. Target population People aged 4 years and over with diabetes mellitus who use multiple daily injections of insulin. Proposed benefits of the technology The proposed benefits of the technology include increased frequency of self-monitoring blood glucose. It is suggested by the manufacturer that this will enable patients to achieve better glycaemic control and thus, improve health outcomes. It is proposed that these improvements will reduce the burden of diabetes-related complications and ultimately yield cost savings for the HSE. Clinical effectiveness The assessment of clinical effectiveness was based on two company-sponsored open-label, twoarmed randomised controlled trials, with a total of 465 participants (Bolinder et al. 2016; Haak et al. 2017). Both trials compare use of the FreeStyle Libre system to SMBG in adults aged 18 years over a six month period. Neither patients nor investigators were blinded to group allocation. The IMPACT trial included people with type 1 diabetes who were performing SMBG regularly ( 3 times per day) and had good glycaemic control (HbA1c 7.5%). The REPLACE trial included people with type 2 diabetes, using multiple daily injections of insulin, who were performing SMBG regularly ( 3 times per week) and had poor glycaemic control (HbA1c 7.5%-12.0%). Both studies report significant improvements in various measures of hypoglycaemia and time in range in the intervention arm. In the REPLACE trial these improvements persisted until the end of the 12 month open-access phase of the study. Both studies report a reduction in the mean number of SMBG test per day in the intervention group (IMPACT: 5.5 [SD 2.0] per day at baseline to 0.5 [SD 0.7] per day at 6 months; REPLACE: 3.9 [SD 1.4] per day at baseline to 0.3 [SD 0.3] at 6 months). The intervention arm in both studies exceeded all glucose monitoring guidelines. In the IMPACT trial, the mean number of sensor scans per day was 15.1 (SD 6.9). In the REPLACE trial, the mean number of sensor-scans per day was 8.3 (SD 4.4), (median 6.8). 2 P a g e

Both studies report a high user and healthcare professional satisfaction with product. However, appraisal of the evidence identified the following limitations: In both trials, scanning frequency was not correlated with observed outcomes. HTAG requested additional data on diet and physical activity; however this information was not available. Therefore it is not possible to infer if or how use of the system led to improvements in diabetes management. During both trials, the intervention group received more support compared to the control group. Therefore the observed differences in hypoglycaemia between groups may in part, be explained by this additional treatment. The results from both trials are not generalizable to those from a lower socioeconomic status and those with type 1 diabetes who are less-well-managed. In addition, it is unclear whether trial participants are representative of the target population in Ireland. It is unclear whether data from these trials are generalizable to children. Both trials were conducted over a six months period; therefore there is insufficient evidence to support whether the observed outcomes would be sustained over a longer period or whether use of the Freestyle Libre will improve long term outcomes for people with diabetes. Device safety Generally, evidence pertaining to the safety of the FreeStyle Libre system among adults aged 18 years and over is satisfactory. During the IMPACT trial, 8% of FreeStyle Libre sensor users reported 13 device-related adverse events and there were 248 sensor insertion-site signs and symptoms experienced by 65 participants (itchiness/rash allergy, erythema and oedema). During the REPLACE trial, 4% of Freestyle senor users reported nine device-related adverse events (itchiness/rash allergy, erythema and oedema). The safety of the FreeStyle Libre in those aged between 4-17 years and during pregnancy has been assessed in two uncontrolled one-armed trials: Edge et al (2017) reported that the FreeStyle Libre was safe to use in those aged 4-17 years. Over a 14 day period, five participants (aged 6, 9, 10, 12 and 15 years) reported five device related adverse events; which included: allergic reaction, blister, pink mark/scabbing and abrasion on sensor removal. Moderate erythema was observed on 11.6% of occasions, mild erythema and pain 13.6% and 4.1%, respectively, and mild instances of bleeding, bruising, itching and oedema were each on <3% of occasions. These findings are limited by a small sample size (total n=89; 4-7 years n= 24; 8-12 years n= 39; 13-17 years n= 26) and a short study duration (14 days). Scott et al. (2017) reported that the FreeStyle Libre was safe to use during pregnancy. 3 P a g e

Study duration or the number of device related events was not reported in the conference abstract. However, similar to Edge et al (2017), findings of this study are limited by a small sample size (n=74). Budget impact A budget impact analysis was undertaken to estimate the annual budget requirements of including the Freestyle Libre system for reimbursement in Ireland. A VAT rate of 23% was applied to costs. The budget impact was calculated as the incremental budget impact for each of the first five years after the introduction of the technology. The parameters used in analysis include are shown in Tables 1 and 2. Table 1 Parameters used in budget impact analysis: Best case scenario 14 day sensor wear / 90% reduction versus 6.2 HTAG tests/ day 50% uptake Acquisition costs FSL Cohort Cost of FSL sensor 59.90 Average cost per SMBG strip dispensed (PCRS) 0.65 Average cost per lancet dispensed (PCRS) 0.11 Optium strip 0.50 Average cost per lancet 0.11 Total Cost Per SMBG Test 0.62 No of SMBG test per day 90% reduction vs. 6.2 HTAG supplied data 0.62 Cost per FSL patient per year 1,696.60 The parameters for the best case scenario were based on the HSE reimbursing a maximum of 26 sensors per year, and all replacement units being provided by Abbott. It is also dependent on the HSE realising the benefit of the expected 90% reduction in SMBG monitoring, and on the cost of blood glucose monitoring strips suitable for use with the FSL reader staying at current cost or lower. The same also applies for Ketone strips associated with the FSL reader. In this scenario, the average additional cost per patient per year for using FSL is 62.60. The benefit to the patients for this cost is an expected reduction in the need to perform finger prick testing of over 2000 times per year. In addition, there is reasonably good evidence that time spent in hypoglycaemia would be reduced. Table 2 Parameters used in budget impact analysis: Worst case scenario 9.3 day sensor wear / 80% reduction versus 6.2 HTAG tests/ day 50% uptake Acquisition costs FSL Cohort Cost of FSL sensor 14 day wear 59.90 Average cost per SMBG strip dispensed (PCRS) 0.65 Average cost per lancet dispensed (PCRS) 0.11 Optium strip 0.50 Average cost per lancet 0.11 Total Cost Per SMBG Test 0.62 No of SMBG test per day 80% reduction vs. 6.2 HTAG supplied data 1.24 Cost per FSL patient per year 2,614.49 4 P a g e

The parameters for the worst case scenario were based on the HSE reimbursing all sensors and the average days per sensor being 9.3 days 1, which was derived from the actual usage during the IMPACT and REPLACE trials. In addition, a less ambitious reduction of 80% in SMBG was assumed. In this scenario, the average additional cost per patient per year was estimated to be 980. The benefits to the patient are the same as in the best case scenario, with a slight reduction in the number of finger prick tests averted. Based on the range of scenarios presented, the company submitted a revised budget impact analysis (Tables 3-5). Analysis is based on an assumed uptake of 30% in the first year of use rising to a maximum of 50% uptake by year 5, based on an assumption by the company that approximately 50% of MDI Diabetes patients will not use, or continue to use the device. Table 3 Annual cost of SMBG among people aged 4 years and over using fast acting insulin Year 1 Year 2 Year 3 Year 4 Year 5 MDI Patients 16838 16838 16838 16838 16838 SMBG Costs 27,513,292 27,513,292 27,513,292 27,513,292 27,513,292 Table 4 Best case scenario 14 day wear/90% Year 1 Year 2 Year 3 Year 4 Year 5 reduction in SMBG MDI Patients 16838 16838 16838 16838 16838 Potential MDI 8419 8419 8419 8419 8419 % uptake 30% 35% 40% 45% 50% Patients using Libre 5,051 5,893 6,735 7,577 8,419 Patients SMBG 11,787 10,945 10,103 9,261 8,419 Cost Per year Libre 8,570,208 9,998,576 11,426,944 12,855,312 14,283,680 Cost Per year SMBG 19,259,304 17,883,640 16,507,975 15,132,311 13,756,646 Total Cost 27,829,512 27,882,216 27,934,919 27,987,622 28,040,326 Increase YoY 0.19% 0.19% 0.19% 0.19% Variance to SMBG -316,220-368,924-421,627-474,330-527,034 % Var vs. SMBG -1.1% -1.3% -1.5% -1.7% -1.9% 1 It should be noted that Abbott contended this figure and were of the opinion that this figure did not reflect sensor duration in a real-life situation. 5 P a g e

Table 5 Worst case scenario 9.3 day wear/80% Year 1 Year 2 Year 3 Year 4 Year 5 reduction in SMBG MDI Patients 16838 16838 16838 16838 16838 Potential MDI 8419 8419 8419 8419 8419 % uptake 30% 35% 40% 45% 50% Patients using Libre 5,051 5,893 6,735 7,577 8,419 Patients SMBG 11,787 10,945 10,103 9,261 8,419 Cost Per year Libre 13,206,825 15,407,962 17,609,100 19,810,237 22,011,374 Cost Per year SMBG 19,259,304 17,883,640 16,507,975 15,132,311 13,756,646 Total Cost 32,466,129 33,291,602 34,117,075 34,942,548 35,768,020 Increase YoY 2.54% 2.48% 2.42% 2.36% Variance to SMBG -4,952,837-5,778,310-6,603,783-7,429,256-8,254,728 % Var vs. SMBG -18.0% -21.0% -24.0% -27.0% -30.0% Expert opinion of the technology Letters of support from seven Healthcare Professionals working in the area of diabetes in Ireland were included with Abbott s application. This information provides an insight to potential benefits of using the product and how the product works in a real-life setting. All of the healthcare professionals were in favour of the reimbursement of the FreeStyle Libre flash glucose monitoring system. They believe that the Freestyle Libre system has the potential to lead to a number of clinically important benefits, such as better glycaemic control. Some have observed improvements in diabetes management and quality of life in patients that have used the product. In their experience, the output produced by the reader enables the consultation process because it provides a clinically actionable result which allows more individualisation of therapy. They consider the product would be of benefit to all patients with diabetes using multiple daily injections; however those who would benefit the most include: Young people with type 1 diabetes Parents or carers of children with type 1 diabetes People who struggle with SMBG People who lead active lives People who have poor hypoglycaemic awareness Organisational implications The evidence suggest that use of the FreeStyle Libre system and associated informatics may facilitate the easier sharing of glucose insights between patients and clinicians (and between clinicians in the care team), enabling more informed clinical decision making. 6 P a g e

However during the initial implementation of the FreeStyle Libre system It is unclear how much time, in terms of HSE resources, will be needed. Healthcare professionals involved in diabetes care will need information about the product and will also require training. Software for the product must be downloaded onto computers; this may potentially impact on IT departments within the HSE. The use of the Freestyle Libre could add to interactions with health care professionals due to increased adverse events and device reading. It is possible that some patients may need a lot of support using the sensors (i.e. need help from a practice nurse). Conclusions The evidence suggests that, compared with SMBG alone, using the Freestyle Libre may facilitate better glycaemic control, in terms of hypoglycaemia, among certain sub-groups. Expert opinion considers the reduction in hypoglycaemia, observed in IMPACT and REPLACE, are of clinical importance. There is limited data to support the routine use in people who are less well managed or in children and young people. The evidence suggests that using FreeStyle Libre may reduce the average number of SMBG tests needed and may facilitate an increase in the frequency of self-monitoring blood glucose. Use of the Freestyle Libre is likely to reduce the need for finger prick testing in patients in the order of 1-2000 times per year. There is insufficient evidence to demonstrate that use of the Freestyle Libre will lead to reduced ambulance call outs, Accident and Emergency usage or hospital admissions related to poor glucose control or will result in long-term improvements in patient outcomes. There are currently no high-quality, peer-reviewed studies that compare the Freestyle Libre system with CGM. There is insufficient evidence to suggest that the system is safe to use in the younger population and during pregnancy. Although, expert opinion sought by the HTA Expert Group suggests that there is no evidence of harm to patients. Based on the data presented, there is insufficient evidence to support the claim that the FreeStyle Libre could yield savings for the HSE. 7 P a g e

Recommendations Based on the report of the HTAG the Health Technology Assessment Expert Group recommend the following: 1. The Freestyle Libre represents an innovative way of managing Diabetes requiring Multiple Daily Injections, and as such represents an advance in diabetes care. 2. Reimbursement for the device should be considered, but it is important that the conditions favourable to the best case scenario presented above are maintained. 3. This decision should be evaluated after one year, in the light of cost analysis and any additional evidence for effectiveness of the device (in particular in relation to longer term patient outcomes). 4. Risk sharing by way of limiting reimbursement to 26 sensors per year by the HSE, with the risk from faulty or unsatisfactory device life being borne by the company should be considered as part of any agreement. 5. Careful patient selection should be part of the agreement, with hospital consultant initiation, and preference for children and young adults in the first instance so that numbers being treated do not exceed that expected. 6. The cost of blood glucose and urine Ketone strips suitable for use with the device should be agreed as part of the overall agreement. 7. After a period of one year data on costs incurred by patients using the device in the PCRS system should be reviewed to ensure that costs are in line with expectations, and to help inform the continuation or otherwise of reimbursement. Advice context: The status of HTAG Advice Notes is required to consider. No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of HTAG at the date of first publication. The content of this Advice Note was based upon the evidence and factors available at the time of publication. Readers are asked to consider that new evidence may have emerged since first publication. 8 P a g e