Post-market Review Products Used in the Management of Diabetes Report to Government Stage 2: Insulin Pumps February 2015

3.5 Inter-Departmental Working Group

Key issues discussed by the Inter-Departmental Working Group include:

• 
  Members noted the need for consistency between guidelines and clinical practice in the management of diabetes.
  
• 
  Members considered the impacts that changes to the Insulin Pump Programme may have on private health insurance markets.
  
• 
  Members discussed the possible pathway for new insulin pump technologies to request listing on the Prostheses List through existing PLAC processes.
  

• 
  Members recommended the inclusion of Aboriginal and Torres Strait Islander, and rural and remote, identifiers in the data collection for the Insulin Pump Programme.
  
• 
  At the request of the Reference Group, the TGA representative provided information on the safety and regulation of insulin pumps and the listing of insulin pumps on the ARTG for inclusion in this Report (refer to Part 2.9).
  

3.6 Reference Group

As a result of Reference Group input, the following actions were taken:

• 
  An extension to the literature review to include observational evidence, which may be more suitable than trial evidence to identify any patient relevant outcomes from insulin pump therapy.
  
• 
  The Department wrote to APEG to seek additional specialist clinician advice on:
  
  • 
    what features of an insulin pump are vital in achieving the best clinical outcomes for paediatric patients and their families;
    
  • 
    which patient sub-groups, from a clinical outcomes perspective, might benefit the most from insulin pump therapy in order to help to prioritise patients under the Programme; and
    
  • 
    what eligibility criteria for the Insulin Pump Programme are necessary to ensure the best possible patient outcomes.
    
• 
  Inclusion of an option for insulin pump discontinuation rates and reasons to be gathered in the data collection for the Insulin Pump Programme.
  
• 
  Inclusion of observational studies on the use of insulin pump therapy in pregnant women with type 1 diabetes.
  
• 
  Inclusion of research on the importance of glycaemic variability as an independent factor in the development of diabetes complications.
  
• 
  Inclusion of research on bolus type delivered by an insulin pump and the effect on postprandial glycaemia.
  

3.7 Advice from the Australasian Paediatric Endocrine Group (APEG)

The APEG advised that the most important features of a pump will vary based on patient needs, and therefore the treating team should be able to determine the most appropriate pump for the patient. However, features such as bolus calculators, dose increments suitable for children, and the ability to download data may have additional advantages for the paediatric population. They stated that features such as continuous glucose monitoring and algorithms to detect hypoglycaemia and suspend insulin delivery provide additional safety and efficacy advantages.

The APEG indicated that the current eligibility criteria are appropriate for children, that there is insufficient evidence on which to base any additional criteria or prioritisation rules, and ideally, there should not be an age cut-off for the Programme. There are risks to creating eligibility criteria without strong clinical evidence to support the restrictions. Without evidence, such prioritisation is likely to result in inequitable distribution of pump use.

Commenting on the system in the United Kingdom, where adolescents are required to undertake a trial of multiple daily injections sometime between the ages of 12 and 18, APEG indicated that this may restrict insulin pump use to those who fail multiple daily injections, and undervalues the potential benefits of pump therapy for those who can also successfully use multiple daily injections.

A recent study by Johnson (2013), an Australian case-control analysis of children and adolescents using pump therapy, demonstrated the benefits of pump therapy, particularly for those with poor control of their diabetes prior to initiating pump treatment. Although this is an observational study, RCTs are generally of shorter duration with fewer subjects, and therefore the case-control study represents some of the best evidence available relating to pump therapy.

Part 4 – ToR 8
Benefits and safety of insulin pump therapy

Determine the clinical outcomes (e.g. HbA_1c, health-related quality of life, and other potential benefits) and harms for people with type 1 diabetes of insulin pump therapy. In this, consideration should be given to different age groups, with a particular reference to those under 18 who may be eligible for the Insulin Pump Programme, which is funded by the Australian Government.

4.1 Key findings for ToR 8

Literature review of RCTs

• 
  The outcomes of the systematic literature review of RCTs (n = 31) showed that the trial evidence could not conclusively support the superior efficacy (measured by HbA_1c levels) or safety (measured by number of hypoglycaemic events) of insulin pump therapy compared to multiple daily injections in any age group. None of the trials assessed long-term health outcomes.
  
• 
  The studies reported a modest improvement in HbA_1c levels in adults, adolescents and children with the use of insulin pump therapy compared to multiple daily injections. In children and adolescents, the improvement in HbA_1c ranged from 0.22% to -0.1%, but only one of the four metaanalyses located demonstrated a statistically significant difference. In adults, HbA_1c improved by -0.30% to -0.19% and all three meta-analyses showed statistical significance. The difference did not reach the 0.5% reduction generally accepted to be of clinical significance (Clar 2010; Cummins 2010). However, there is no consensus on this issue and a smaller reduction may be considered important from a public health perspective if achieved on a wide scale (Farmer 2012).
  
• 
  The RCTs for children had low evidence strength due to small sample size, lack of participant and personnel blinding due to the nature of the intervention, and funding by insulin pump manufacturers.
  
• 
  In children and adolescents, the literature review found that the reported quality of life outcomes were better with insulin pump therapy compared to multiple daily injections in five studies. However, only two of the five RCTs showed a statistically significant increase favouring insulin pump therapy.
  
• 
  In adults, the literature review (n = 6 RCTs) found that reported quality of life was better with insulin pump therapy than multiple daily injections, with statically significant differences observed in four RCTs. A number of assessment tools were used including the Diabetes Treatment Satisfaction Questionnaire, Diabetes Quality-of-Life questionnaire, and the Medical Outcomes Study 12-Item and 36-Item Short-Form Surveys.
  
• 
  No sub-group analyses in the identified systematic reviews considered characteristics of children other than age.
  

Literature review of observational studies

• 
  There are a number of important limitations to interpretation of benefit from observational studies associated with the lack of randomisation and blinding, and high risk of selection and publication bias. It is not possible to compare the real difference between multiple daily injections and insulin pump therapy using observational studies independent of confounding factors. However, due to study inclusion and exclusion criteria, patients included in these studies may be more representative of use in Australian clinical practice than those in RCTs.
  
• 
  The systematic literature review of observational evidence indicates that children, adolescents, and adults appear to achieve greater reductions in HbA_1c with insulin pump therapy than with multiple daily injections. In the majority of studies, statistically significant reductions in HbA_1c were found to be maintained over several years.
  
• 
  Of the thirteen before-and-after studies and nine cohort studies in children and adolescents, sixteen showed statistically significant reductions or end of study differences in HbA_1c favouring insulin pump therapy. In the before-and-after studies the significant mean difference in HbA_1c ranged from -0.3% to -1.04% (where reported).
  
• 
  In the fifteen observational studies in adults, twelve showed statistically significant reductions or end of study differences in HbA_1c favouring insulin pump therapy. In the before-and-after studies the significant mean differences in HbA_1c ranged from 0.4% to 2.6%.
  
• 
  The reductions in HbA_1c were shown to be greater in patients with high initial HbA_1c levels (Aberle 2008; Shalitin 2010; Johnson 2013), and two studies reported that insulin pump therapy seems more beneficial when initiated in children under six years old (Hughes 2012; Levy-Shraga 2013).
  
• 
  Where reported, most observational studies showed lower risks of severe hypoglycaemia with insulin pump therapy in children, adolescents and adults, with most evidence found in children.
  
• 
  Of six observational studies of glycaemic variability, all demonstrated statistically significant results favouring insulin pump therapy in reducing glycaemic variability.
  
• 
  Of ten retrospective cohort studies in pregnant women with type 1 diabetes, most did not show significant differences between multiple daily injections and insulin pump therapy on diabetes management, maternal pregnancy outcomes or newborn outcomes. Limitations of the studies included low patient numbers and lack of adjustment for differences between the cohorts or confounding factors. In addition, poor glycaemic control may have been an indication for insulin pump therapy in some studies.
  

Stakeholder input

• 
  Drawing on information from the written submissions and the Stakeholder Forum, the overall sentiment from consumers, consumer groups and manufacturers is that there are clinical benefits from using insulin pump therapy. Improvements in effectiveness, safety and quality of life were reported in the public submissions.
  

• 
  Clinical groups expressed that while the randomised trial and observational study evidence does not conclusively support the superior outcomes of insulin pump therapy, there is some benefit in particular patient sub-groups, including high-risk patients.
  
• 
  It was explicit that the success of either insulin pump or multiple daily injection therapy was dependent on the level of motivation and subsequent compliance of the patient and/or carer.