Hybrid closed loop systems for managing blood glucose levels in type 1 diabetes

People with type 1 diabetes, families and carers

3.1 Patient experts explained that the mental load of living with diabetes is significant. This is because people with diabetes (and their parents or carers) look at a lot of data and have to make a lot of calculations and decisions about their insulin dose every day. This can be exhausting, affect people's mood and frequently leads to burn out. People with diabetes and their families can also be woken by continuous glucose monitor (CGM) alarms, causing sleep disruption. The patient experts explained that managing glucose levels is a lot of work and can affect home life, education, training or work. Although a CGM and continuous subcutaneous insulin infusion (CSII) can help maintain blood glucose control, if they are not integrated then this still involves substantial user input, which can be a mental burden. A parent of a child with diabetes said that the mental burden significantly affected their quality of life. They highlighted that children are less able to recognise the symptoms of hypoglycaemia and hyperglycaemia, and this is a constant worry for parents when they are apart from their children. They also explained that disrupted sleep was a significant problem, with parents waking multiple times a night to monitor their child's blood sugar and administer glucose or insulin. The committee concluded that managing type 1 diabetes is a substantial mental burden on people with diabetes and their families. It further concluded that automated technologies such as hybrid closed loop (HCL) systems can reduce some of the burden, and improve quality of life for people, their families and carers.

Access to technology and care

3.2 Access to technology and appropriate care was highlighted by patient experts as a major concern, and they explained that the process was often slow, frustrating and demoralising. Patient and clinical experts said that there is a postcode lottery in access to technology. Also they noted that there are inequality issues related to family background and socioeconomic status. Clinical experts said that the automation offered by HCL systems could help reduce some of the inequalities for people who find it difficult to maintain healthy blood glucose levels because of a language barrier, a lower level of education or a learning disability, for example. A clinical expert said that NHS England (NHSE) has set out priorities for access to help reduce these healthcare inequalities. A clinical expert also highlighted that the effective use of technologies was an important consideration. They said that improvements to the availability of and access to patient training were needed. They noted that many centres were limited because they do not have enough trained staff in their clinical teams to provide this. The committee concluded that improvements were needed to make sure there was no postcode lottery in access to technology and care. It further concluded that people should be supported to use the systems.

Evidence and generalisability

3.3 The external assessment group (EAG) used 3 different sources to assess the clinical effectiveness of HCL systems. These were randomised controlled trials (RCTs), NHSE study data from adults (the NHSE adult pilot study), and NHSE study data from children and young people (the NHSE children and young adult pilot study). A clinical expert said that they had some concerns about patient recruitment in the RCTs. They noted that people in RCTs usually have more motivation and a better ability to self-manage their diabetes than some people with diabetes in the NHS. The committee also heard that the RCTs were small in terms of patient numbers and were heterogeneous. Most RCTs included children and young adults. A clinical expert said that most people using CSII in their clinics were adults. The EAG said that the NHSE pilot studies had limitations, because they were non-randomised with a before and after study design and no control group. But the clinical experts explained that the strengths of the pilot studies were that they included a broader range of people than are usually recruited to RCTs. One clinical expert explained that the NHSE adult pilot study selected centres from around the country, but these were skewed towards adults in lower socioeconomic areas. Some clinical experts and committee members said that the populations in the NHSE pilot studies were a better reflection of populations in NHS practice. This was because they included people who may find it difficult to meet glucose targets and who may experience more severe physical and psychological effects of type 1 diabetes. The committee concluded that both the RCTs and the NHSE adult pilot study were not fully generalisable to the type 1 diabetes population in the NHS.

Baseline characteristics

3.4 The baseline HbA1c levels differed between the RCTs and the NHSE adult pilot study. The people in the RCTs had lower HbA1c levels at baseline (56 mmol/mol to 67 mmol/mol [7.3% to 8.3%]) than in the NHSE adult pilot study (around 79 mmol/mol [9.4%]). A clinical expert explained that National Diabetes Audit data shows that over 65% of people with type 1 diabetes have an HbA1c of over 58 mmol/mol (7.5%). Clinical experts explained that people with higher HbA1c levels at baseline would be expected to have a greater reduction after treatment. The network meta‑analysis showed that HCL systems were associated with a decrease in HbA1c of 3.1 mmol/mol (-0.29 percentage points) compared with CSII plus CGM. But the NHSE adult pilot study reported a decrease in HbA1c of 16.2 mmol/mol (-1.5 percentage points). Some clinical experts said that they preferred the NHSE adult pilot baseline and HbA1c effect, because this was a better representation of real-world NHS practice. The committee concluded that for many people with type 1 diabetes in the NHS, the baseline HbA1c would likely be higher than that reported in the RCTs, so HCL systems may reduce HbA1c more than that estimated from the RCT network meta-analysis. But the extent of the difference was highly uncertain. The committee further concluded that differences in baseline HbA1c levels between the RCTs and NHSE pilot studies led to substantial differences in the reported HbA1c change.

Children

3.5 The EAG's subgroup analyses showed that in the RCT children and young adults (under 18 years) subgroup, the change in HbA1c for HCL systems was greater (-0.31 percentage points, 95% CI -0.43 to -0.20) than the adult subgroup (-0.24 percentage points, 95% CI -0.32 to -0.15). The NHSE children and young people pilot had a lower baseline HbA1c of around 62 mmol/mol (7.9%) compared with the adult pilot study. The decrease in HbA1c after using HCL systems was also lower than the adult pilot, at 7 mmol/mol (-0.7 percentage points) after using HCL systems for 6 months. Data was not presented on age groups specified in the NICE scope for HCL in type 1 diabetes (that is, 5 years and below, 6 to 11 years and 12 to 19 years). A clinical expert explained that in the NHSE children and young people pilot, child age subgroups were not reported because of the low numbers of children in certain age groups that were using devices.

Pregnancy

3.6 There was only 1 small study on HCL systems' effectiveness in pregnancy. The EAG said that it was difficult to draw firm conclusions in this population. But the committee thought that there could be greater benefits of HCL systems in pregnancy, because blood glucose control is harder to maintain and there is a risk to both the mother and unborn baby. A clinical expert said that HbA1c is a less effective clinical measure of diabetes control in pregnancy. The committee noted that it would be difficult to do studies of HCL systems in pregnancy because the duration of pregnancy is relatively short. This would complicate study design and data collection. The committee concluded that there was a lack of evidence in pregnancy and relevant studies would be difficult to do. It further concluded that the effectiveness of HCL systems in pregnancy would likely be greater than in the overall population.

Baseline characteristics and HbA1c effects

3.7 In its base-case model, for the key baseline characteristics the EAG used data from the 2019 to 2020 National Diabetes Audit subgroup for those on CSII. The baseline HbA1c from this data was 64 mmol/mol (8.0%) and the EAG applied the estimated HbA1c decrease from the RCT network meta-analysis of 3.1 mmol/mol (-0.29 percentage points). In separate scenario analyses the EAG used the NHSE adult pilot study baseline characteristics, with an HbA1c baseline of 79 mmol/mol (9.4%), and applied the HbA1c decrease from either the RCT network meta-analysis (3.1 mmol/mol [-0.29 percentage points]) or the NHSE pilot (16.2 mmol/mol [-1.5 percentage points]). The committee heard that when the NHSE adult pilot baseline characteristics and HbA1c effect were used, the resulting incremental cost-effectiveness ratio (ICER) was substantially lower than the base case (£12,398 compared with £178,925 per quality-adjusted life year [QALY] gained). The EAG provided an analysis of HbA1c net improvement using both the National Diabetes Audit CSII patient baseline characteristics and the NHSE adult pilot baseline characteristics. The committee said that this was useful to help understand how the ICER would change with different changes in HbA1c. The committee noted that a baseline HbA1c of 79 mmol/mol (9.4%) and a reduction of 16.2 mmol/mol (-1.5 percentage points) showed HCL systems to be cost effective. But it said that using this data in the model would be equivalent to restricting HCL system access to people with much higher than average HbA1c levels. The committee preferred a baseline HbA1c of 64 mmol/mol (8.0%) for use in the model as this widens access to people who cannot maintain their target HbA1c resulting in them having an HbA1c of around 64 mmol/mol (8.0%). The committee said that that the change in HbA1c reported in the NHSE adult study pilot was a good representation of what could be achieved for people with higher HbA1c levels. It also noted that the RCTs showed that people with lower HbA1c levels could also benefit. The committee concluded that with a baseline HbA1c of 64 mmol/mol (8.0%), the expected reduction in HbA1c after HCL system use could be greater than 3.1 mmol/mol (-0.29 percentage points) but would be lower than the 16.2 mmol/mol (-1.5 percentage points) from the NHSE pilot. But it was unclear where in this range the effect estimate would lie. Without any directly observed data, a decrease of 3.1 mmol/mol (-0.29 percentage points) was a reasonable estimate. It further concluded that the change in HbA1c substantially affected the ICER, and therefore whether HCL systems could be considered cost effective.

Comparators

3.8 The population in the economic model was people on a single technology (CSII, rtCGM, or isCGM). In the model they could then move to a non-integrated system or to HCL. The comparators used for the economic modelling were rtCGM plus CSII (non-integrated) and isCGM plus CSII (non-integrated). NICE's guideline on type 1 diabetes in adults recommends that people should be offered either rtCGM or isCGM, based on their individual preferences. A clinical expert explained that around 80% of people now have a CGM device. In the economic model base case, the EAG grouped the comparator technologies together as CGM plus CSII and assumed 90% of people were on isCGM and 10% were on rtCGM. Clinical experts explained that in the clinical-effectiveness evidence, when it was reported, all comparators in the RCTs used rtCGM. They also said that rtCGM and isCGM are not the same in terms of cost or clinical effectiveness. So the model may have underestimated the cost effectiveness of HCL systems by comparing them with the clinical effectiveness of rtCGM, but with the lower cost of isCGM. But some experts said that the performance of the newer isCGMs is closer to that of rtCGMs. Although the comparator in the assessment was CGM plus CSII, clinical experts explained that there is a delay in getting people onto CSII, with around 75% of people with diabetes nationally not having CSII. It concluded that although this may have underestimated the cost effectiveness of HCL systems, it was likely that if HCL systems were recommended, they would displace both rtCGM plus CSII (non-integrated) and isCGM plus CSII (non-integrated).

Uncaptured benefits

3.9 In the economic model, non-severe hypoglycaemic events and severe hypoglycaemic events were only included in a scenario analysis. The EAG said that there was high uncertainty around these annual event rates. When hypoglycaemic events were included, the ICERs were reduced and ranged from £120,679 per QALY gained to £170,193 per QALY gained, depending on the annual event rate and what source the EAG used for the hypoglycaemic event disutility values. In the EAG's exploratory modelling for children and young people, a scenario analysis included the quality of life effects of using HCL systems. This considered the improvements reported in the hypoglycaemia fear survey. The hypoglycaemia fear survey is an 18-item questionnaire that assesses the levels of fear related to hypoglycaemia. Each item is measured on a 5‑point scale from 0 (never) to 4 (almost always). Individual item scores can highlight someone's major concerns about hypoglycaemia. This reduced the ICER of the NHSE children and young people pilot scenario (which used the NHSE children and young people pilot baseline characteristics and HbA1c change). A further scenario analysis tripled the quality of life effects reported in the hypoglycaemia fear survey and applied this for 15 years to account for 2 parents having a similar quality of life improvement. This reduced the ICER further still (see section 3.11). However, clinical experts expressed concerns that the reduced mental burden and familial or carer anxiety that HCL systems provide may not be captured adequately in the model. The committee understood that there was no quantitative evidence that could be used to estimate the value of these potential quality of life benefits. The committee agreed that there were potential quality of life benefits of HCL systems not captured in the model, including the effect on learning and education, ability to work, mental burden and fear of hypoglycaemic events. The committee concluded that these uncaptured benefits were likely to undervalue the effect of HCL systems on quality of life.

Time horizon and long-term effects

3.10 In the base-case economic model, the time horizon was 60 years and the effect on HbA1c was assumed to last for the duration of the model. The time horizon and HbA1c effect duration were key drivers of the model results. Scenarios that reduced the time horizon or duration of the HbA1c effect all resulted in higher ICERs. Some clinical experts said that they would expect the improvements in HbA1c to be maintained. The EAG said that the incidence of kidney and eye complications may be overestimated in the model, and there was uncertainty around the modelling of these long-term effects. The committee concluded although there were uncertainties in the modelling of long-term effects and that this may have overestimated the cost effectiveness, they agreed with the time horizon of 60 years and the lasting HbA1c effect.

Cost effectiveness for children

3.11 The EAG's exploratory modelling in children and young people showed that HCL systems appear to be more cost effective than in adults, with a base-case ICER of £168,196 per QALY gained. When the analysis was limited to the RCTs in children, the ICER was reduced to £116,256 per QALY gained. In a scenario that used the NHSE children and young people pilot baseline characteristics and HbA1c decrease of 7 mmol/mol (-0.7 percentage points), there was a substantial reduction in the ICER to £54,727 per QALY gained. The EAG said that there was some uncertainty in the results of the exploratory modelling in children. This was because of uncertainty around the modelled long-term survival and also uncertainty around how much clinical data from children was used in the model. The committee concluded that although there was some uncertainty, HCL systems are likely to be more cost effective for children than adults.

Cost effectiveness in pregnancy

3.12 There was a lack of evidence about the cost effectiveness of HCL systems in managing blood glucose in pregnancy for people with type 1 diabetes. But the committee recalled that the effectiveness of HCL systems in pregnancy would likely be greater than in the overall population (see section 3.6). So HCL systems would likely be cost effective when used in pregnancy and for people planning a pregnancy.

Costs in the economic model

3.13 The committee considered an analysis including confidential prices submitted to NHS supply chain by the companies. It noted that use of these prices resulted in lower ICERs but not to within the range that would be considered a cost-effective use of NHS resources by NICE. The committee also considered a threshold analysis on average 4-year costs to help them understand the effect of costs of HCL systems on the ICER (see section 2). It noted that relatively small reductions in costs resulted in large reductions in the ICER. The committee concluded that the cost of the HCL systems was a key driver of the cost-effectiveness results.

ICER per QALY gained

3.14 NICE's guide to the methods of technology appraisal 2013 notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the following aspects of the model affect the ICER:

Many of the scenarios tested by the EAG resulted in ICERs much higher than NICE would consider to be cost effective. There is uncertainty around the assumptions that should be used in the base case, so there is a risk of decision error. So it agreed that an acceptable ICER would be around £20,000 per QALY gained.

Innovation

3.15 The committee considered whether HCL systems are innovative. It noted that these systems enhance existing devices by using an algorithm to integrate rtCGM data with CSII. The committee concluded that although HCL systems provide an alternative treatment option for people with type 1 diabetes, the level of innovation is not sufficient to justify consideration of a higher ICER (over £20,000 per QALY gained).