The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using empagliflozin combination therapy in the NHS in England. The Appraisal Committee has considered the evidence submitted by the company and the views of non-company consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see section 9) and the public. This document should be read along with the evidence base (the evaluation report).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Please note: this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE's guidance on using empagliflozin combination therapy in the NHS in England.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

• Closing date for comments: 18 September 2014
• Second Appraisal Committee meeting: 24 September 2014

Details of membership of the Appraisal Committee are given in section 8, and a list of the sources of evidence used in the preparation of this document is given in section 9

1   Appraisal Committee’s preliminary recommendations

1.1   The Committee is minded not to recommend empagliflozin within its marketing authorisation as combination therapy with or without insulin for treating type 2 diabetes.

1.2   The Committee recommends that NICE requests further analyses from the company, which should be made available for the second Appraisal Committee meeting, and should include:

• revised estimation of the incremental cost-effectiveness ratios of empagliflozin using a validated economic model, informed by the corrected results of network meta-analyses and compared with relevant comparators (sodium-glucose cotransporter-2inhibitors and dipeptidyl peptidase-4 inhibitors)
• sensitivity analyses which should also include probabilistic exploration of parameter uncertainty.

2  The technology

2.1   Empagliflozin (Jardiance, Boehringer Ingelheim) is an orally administered selective sodium-glucose cotransporter-2 (SGLT-2) inhibitor, which lowers blood glucose in people with type 2 diabetes by blocking the reabsorption of glucose in the kidneys and promoting excretion of excess glucose in the urine.

2.2   Empagliflozin has a European marketing authorisation for the treatment of type 2 diabetes to improve glycaemic control in adults as:

• ‘Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.
• Add-on combination therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control’.

2.3   The recommended starting dosage is 10 mg once daily for both monotherapy and as an add-on combination therapy with other glucose‑lowering medicinal products including insulin.According to the summary of product characteristics, the dosage can be increased to a maximum of 25 mg daily for people who tolerate empagliflozin well and need tighter glycaemic control, if they have an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m² or more.

2.4   The summary of product characteristics states the following adverse reactions for empagliflozin as the most commonly reported: hypoglycaemia in combination with insulin or a sulfonylurea, vulvovaginal candidiasis, urinary tract infection, and polyuria or pollakiuria (that is, urinary frequency). For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.5   According to the company’s submission, the price of empagliflozin (excluding VAT) is £36.59 per pack of 28 tablets for both 10 mg and 25 mg doses. The annual cost of empagliflozin is estimated to be £470.30. Costs may vary in different settings because of negotiated procurement discounts.              

3  The company’s submission

The Appraisal Committee (section 8) considered evidence submitted by the company of empagliflozin and a review of this submission by the Evidence Review Group (ERG; section 9).

Clinical effectiveness

3.1   The company identified 11 studies that evaluated empagliflozin for treating type 2 diabetes. The company’s submission included details of 8 of these 11 studies: 7 randomised controlled trials and 1 long-term extension study (1245.31). The 3 studies excluded were 1 that evaluated empagliflozin as monotherapy (1245.20), EMPA-REG OUTCOM (1245.5) and EMPA-REG-JAPAN (1245.52). The company did not explain why they were excluded. One of the included studies (1245.48) compared empagliflozin with placebo as monotherapy and therefore is not relevant to this appraisal.

3.2   The long-term extension study (1245.31) recruited patients from 3 trials: 2 in which empagliflozin was evaluated as a combination therapy (1245.19 and 1245.23) and 1 monotherapy trial (1245.20). The results were presented separately for the patients from different studies.

3.3   Study 1245.23 comprised 2 separate sub-studies: EMPA-REG-MET, evaluating empagliflozin plus metformin, and EMPA-REG-METSU, evaluating empagliflozin plus metformin and a sulfonylurea. Another study, 1254.19, evaluated empagliflozin plus pioglitazone or pioglitazone plus metformin. Two studies, 1245.33 and 1245.49, evaluated empagliflozin as an add-on to basal insulin and multiple daily injections of insulin respectively, with or without other oral antidiabetic agents.

3.4   Study 1245.36 (in patients with renal impairment) included patients with estimated glomerular filtration rate (eGFR) measurements of less than 60 ml/min/1.73 m². Because the summary of product characteristics restricts the use of empagliflozin in patients with an eGFR less than 60 ml/min/1.73 m², only the subgroup of patients with mild renal impairment (eGFR of 60–90 ml/min/1.73 m²) is relevant for this appraisal.

3.5   All but 1 of the relevant studies had 3 treatment arms: empagliflozin 10 mg, empagliflozin 25 mg and placebo. Study 1245.28 instead compared empagliflozin 25 mg with glimepiride (a sulfonylurea) as a dual therapy on a background of metformin. Study 1245.23 also included an open-label treatment arm comprising patients with very poor glycaemic control whose baseline glycated haemoglobin (HbA_1c) was more than 10%. The patients in this arm had empagliflozin 25 mg.

3.6   The duration of the relevant studies varied from 24 weeks (1245.19 and 1245.23) to 2 years (1245.28). The efficacy and safety results at 76 weeks for patients enrolled in the 1245.19 and 1245.23 trials were available in study 1245.31. The studies evaluating empagliflozin as an add-on to insulin therapy lasted for 78 weeks (1245.33) and 52 weeks (1245.49).

3.7   The primary outcome measure in the trials was change in the levels of HbA_1c from baseline. The results showed that empagliflozin at both doses (10 mg or 25 mg) was associated with a statistically significant reduction in mean HbA_1c compared with placebo in patients on different background therapies, including insulin. These reductions were maintained throughout the duration of treatment in the long-term extension study (1245.31). The glycaemic control achieved with empagliflozin 25 mg in patients with metformin background therapy was statistically non-inferior compared with glimepiride at week 104 in trial 1245.28. Empagliflozin also showed a statistically significantly better reduction in HbA_1c compared with placebo in patients with mild renal impairment (1245.36). The adjusted change from baseline in mean HbA_1c level from the relevant studies is summarised in table 1.

Table 1 Adjusted mean change from baseline in mean HbA1c level (%) ±SE

Trial	Duration	Placebo/active comparator	Empagliflozin 10 mg	Empagliflozin 25 mg
Patients on baseline pioglitazone or pioglitazone plus metformin (dual or triple therapy)
1245.19	At  week 24	−0.11±0.07	−0.59±0.07	−0.72±0.07
	P value	–	<0.0001	<0.0001
1245.31 (patients from study 1245.19)	At week 76	−0.01±0.07	−0.61±0.07	−0.70±0.07
	P value	–	<0.0001	<0.0001
Dual therapy: patients on baseline metformin
1245.23 (metformin only sub-study)	At week 24	−0.13±0.05	−0.70±0.05	−0.77±0.05
	P value	–	<0.0001	<0.0001
1245.31 (patients from 1245.23 metformin only sub-study)	At week 76	−0.01±0.05	−0.62±0.05	−0.74±0.05
	P value	–	<0.0001	<0.0001
1245.28 (compared with glimepiride)	At week 104	−0.55±0.03	–	−0.66±0.03
	P value (non-inferiority)	–	–	<0.0001
Triple therapy: patients on baseline metformin plus SU
1245.23 metformin plus SU sub-study)	At week 24	−0.17±0.05	−0.82±0.05	−0.77±0.05
	P value	–	<0.001	<0.001
1245.31 (patients from 1245.23 metformin plus SU sub-study)	At week 76	−0.03±0.06	−0.74+0.06	−0.72+0.06
	P value	–	<0.0001	<0.0001
Add-on to insulin: patients on baseline insulin ± other anti-diabetics
1245.33	At week 18	−0.01±0.07	−0.57±0.07	−0.71±0.07
	P value	–	<0.0001	<0.0001
	At week 78	−0.02±0.09	−0.48±0.08	−0.64±0.09
	P value	–	<0.0001	<0.0001
1245.49	At week 18	−0.50±0.06	−0.94±0.06	−1.02±0.06
	P value	–	<0.0001	<0.0001
	At week 52	−0.81±0.08	−1.18±0.08	−1.27±0.08
	P value (non-inferiority)	–	<0.0001	<0.0001
Empagliflozin in patients with mild renal impairment
1245.36 (subgroup with mild renal impairment	At week 24	0.06±0.07	−0.46±0.07	−0.63±0.07
	P value	–	<0.0001	<0.0001
	At week 52	0.06±0.08	−0.57±0.08	−0.60±0.08
	P value	–	<0.0001	<0.0001
Abbreviations: HbA1c, glycated haemoglobin; SE, standard error; SU, sulfonylurea

3.8   Important secondary outcomes included change in body weight and blood pressure from baseline. In a study for dual therapy (1245.23 EMPA-REG MET), at week 24 compared with placebo, empagliflozin 10 mg resulted in mean weight loss of 1.6 kg and empagliflozin 25 mg resulted in a loss of 2.0 kg. Similarly, at week 24 in triple therapy (in study 1245.23 EMP-REG METSU) compared with placebo empagliflozin 10 mg reduced weight by 1.8 kg and empagliflozin 25 mg reduced it by 2.0 kg. The long-term extension study (1245.31) confirmed that weight loss from baseline achieved at week 24 was largely maintained at week 76. Both doses of empagliflozin with basal insulin regimens (in study 1245.33) were associated with much greater weight loss compared with placebo at week 78: 3.6 kg for empagliflozin 10 mg and 3.1 kg for empagliflozin 25 mg. In combination with multiple daily injections of insulin (1245.49), compared with placebo empagliflozin reduced mean body weight by 2.39 kg (10 mg) and 2.48 kg (25 mg). Reductions in systolic blood pressure ranged from 1.4 mm Hg in the 1245.49 trial to 4.8 mm Hg in the metformin‑only sub-study of trial 1245.23.

3.9   Health-related quality of life data were collected in 6 trials that compared empagliflozin with placebo (including a trial of empagliflozin as a monotherapy, 1245.20). The mean EQ-5D utility index score at baseline was comparable across the 6 trials and ranged between 0.791 and 0.813. Across all trials the addition of empagliflozin did not result in a clinically meaningful change in quality of life, with baseline EQ-5D utility index scores being maintained throughout the trials. The company’s submission presents pooled data from the 6 trials at different time points (weeks 4, 6, 12, 18, 24, 40 and 52). The company also stated that no differences in EQ-5D score were evident in any subgroups based on age, sex, BMI, country, blood pressure, HbA_1c level at baseline, eGFR at baseline, prior cardiovascular events, time since diagnosis, race or cardiovascular risk predictor. The trials also collected data using a visual analogue scale (EQ VAS), and the company reported that change from baseline EQ VAS was similar across all treatment groups at all time -points.

3.10   The company’s submission presented adverse events as reported in the individual studies. In general, the proportions of patients who experienced any adverse events, severe adverse events or adverse events leading to discontinuation of trial medication were similar between both empagliflozin groups and placebo across all trials. In most trials, adverse events leading to discontinuation were more frequent in the placebo group than in the empagliflozin groups. Adverse events in more than 5% of patients in any randomised group in the trials were urinary tract infections, balanitis, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, cough, diarrhoea, hypoglycaemia, hyperglycaemia, dyslipidaemia, hypertension, arthralgia, back pain, pain in extremity, headache, dizziness and depression.

3.11   Hypoglycaemic events, urinary tract infection, genital infections, volume depletion and fractures were considered to be ‘adverse events of special interest’ and reported separately. The data showed that treatment with empagliflozin did not lead to an increase in hypoglycaemic events in most trials, except those in which empagliflozin was administered with a sulfonylurea (the 1245.23 EMPA-REG-METSU sub-study and patients moving from the same sub-study in extension study 1245.31) or with insulin as background therapy (1245.33 and 1245.49). Across all trials, genital infections (generally of mild to moderate intensity) were consistently more frequent in the empagliflozin groups than with placebo. The incidence of urinary tract infections was similar across both empagliflozin groups and placebo, although it was reported that empagliflozin was associated with a greater frequency in women compared with placebo. In addition, both genital and urinary tract infections were more common in women than men. The frequency of volume depletion was low across all clinical studies and comparable between all treatment groups. The rates of fracture were very low and similar for all treatment groups across all empagliflozin trials.

3.12   The company’s submission considered dipeptidyl peptidase-4 (DPP-4) inhibitors and other sodium-glucose cotransporter-2 (SGLT-2) inhibitors (dapagliflozin and canagliflozin) to be the comparators for empagliflozin. In the absence of any head-to head trial, the company performed indirect comparisons by means of network meta-analyses. The company conducted a systematic literature review to identify randomised controlled trials that evaluated the comparators. Five networks of randomised controlled trials were considered, each 1 including trials that compared the interventions for patients whose diabetes was no longer responding adequately to:

• metformin (for dual therapy)
• metformin plus sulfonylurea (for triple therapy)
• thiazolidinediones (for dual therapy)
• thiazolidinediones and metformin (for triple therapy)
• insulin therapy plus other oral antidiabetic drugs (as an add-on to insulin therapy).

3.13   The outcomes compared in the network meta-analyses included change from baseline in HbA_1c, systolic blood pressure, and body weight. Safety outcomes were hypoglycaemia (severe and non-severe), urinary tract infection and genital tract infection. For continuous outcomes, Bayesian network meta-analysis was used to determine the mean differences in change from baseline and associated 95% credible intervals between all interventions. For binary outcomes, the proportions of events were modelled in a logistic regression framework, and relative risks and associated 95% credible intervals were estimated.

3.14   Several trials were available in which metformin was background therapy and so an uninformed random-effects model was applied for that network. For the other 4 background therapies (metformin plus a sulfonylurea, thiazolidinedione, thiazolidinedione plus metformin and insulin), all comparisons were based on single trials (except empagliflozin compared with placebo for add-on to insulin). The company used a conventional fixed-effects model to account for heterogeneity in these networks.

3.15   The company presented the outcomes at 24±4 weeks and 52±4 weeks. Results at 52±4 weeks were based on less evidence and were similar to those for 24±4 weeks. For this reason, results at 24±4 weeks were used to inform the base case in the economic modelling (see section 3.30). Results from the indirect comparison showed that empagliflozin was generally comparable to the other SGLT-2 inhibitors. However, the exception was when empagliflozin (either dose) was compared with canagliflozin 300 mg as triple therapy (on background metformin and a sulfonylurea) or when empagliflozin 10 mg was compared with canagliflozin 300 mg as an add-on to insulin therapy. In these comparisons, empagliflozin was statistically inferior to canagliflozin in terms of lowering HbA_1c. Empagliflozin was more likely to result in reductions in body weight and blood pressure when compared with DPP-4 inhibitors in both dual and triple therapy, and also showed better reduction in HbA_1c levels than DPP-4 inhibitors on thiazolidinedione background therapy. The incidence of urinary tract and genital tract infections was comparable between empagliflozin and other treatments.

Evidence Review Group's comments on the company's clinical-effectiveness evidence

3.16   The ERG considered the trials to be good quality but commented that the lack of head-to-head trials against the main comparators (DPP-4 inhibitors or other SGLT-2 inhibitors) was the main weakness of the evidence base. The demographic characteristics were well balanced across treatment groups except in study 1245.49, in which the proportion of men was much lower in the placebo arm than the empagliflozin arms (39.9% placebo, 52.2% empagliflozin 10 mg, 44.2% empagliflozin 25 mg).

3.17   The ERG noted that the company’s submission did not report outcome data on change in lipid levels for any trial, but that change in lipid profiles for studies 1245.19 and 1245.23 had already been published. The results of study 1245.23 showed that in comparison with placebo, both doses of empagliflozin were associated with a statistically significant reduction in most of the components of serum lipids. Study 1245.19 also showed that both doses of empagliflozin reduced high-density lipoprotein cholesterol statistically significantly compared with placebo. The changes in other fractions of lipids were not statistically significant.

3.18   The ERG identified many errors in the company’s network meta-analyses. The ERG commented that the systematic review process was inadequately described, lacking details on inclusion criteria for studies, justification for excluded studies, quality assessment and data extraction process for included studies. The ERG was also concerned that the company had not done any sensitivity analyses or statistical tests.

3.19   The ERG also identified discrepancies between input data, identification of treatments and the codes in the software used for network meta-analyses (WinBUGS). In the ERG’s opinion these were errors, resulting from insufficient scrutiny during the data extraction process. It also noted that the company had not provided all the WinBUGS coding in its submission.

3.20   The ERG also identified that data on overall hypoglycaemia, non-severe hypoglycaemia and urinary tract infections from many studies listed in the network were not used in the actual analysis. The actual analysis performed in WinBUGS also included some data that were not reported anywhere in the submission.

3.21   The ERG had access to an independent, academic, unpublished network meta-analysis comparing the clinical effectiveness of dapagliflozin, canagliflozin and empagliflozin in dual therapy, which found no clinically significant differences between empagliflozin and canagliflozin. After validating some of the company’s revised results at the clarification stage, the ERG largely agreed with the company’s conclusion that empagliflozin’s clinical effectiveness is comparable to that of canagliflozin, dapagliflozin and sitagliptin.

Cost effectiveness

3.22   The company submitted a patient-level state transition model which used Microsoft Excel to store input parameters and to present the model output, but the main calculations were performed using Visual Basic applications. It modelled individual patients’ transitions between health states using a fixed cycle length of 6 months over a 40-year time horizon. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%.

3.23   The patient entered the model with a set of baseline characteristics and modifiable risk factors which included HbA_1c, total body weight, total cholesterol to high-density lipoprotein cholesterol ratio and systolic blood pressure. The value of these variables changed as the model simulation progressed as a result of the effects of antidiabetic treatment and through natural progression, calculated from UK Prospective Diabetes Study (UKPDS number 68) risk equations.

3.24   UKPDS risk equations were also used to predict the occurrence of 7 diabetes-related macro and microvascular complications, and death. Macrovascular events predicted in the model were:

• ischaemic heart disease
• myocardial infarction
• congestive heart failure
• stroke.

Microvascular events predicted in the model were:

• amputation
• renal failure
• blindness in 1 eye.

3.25   The model compared patients who had empagliflozin or comparator treatments. In total, 60,000 simulations were done, considering a sample of 30,000 patients per treatment (300 samples of 100 patients each). Every patient in 1 arm had a corresponding patient in the other, with similar baseline characteristics in terms of age, sex, family origin, smoking status, HbA_1c level, systolic blood pressure, BMI, ratio of total cholesterol to high-density lipoprotein cholesterol, and presence or absence of diabetes complication such as ischaemic heart disease, stroke or blindness in 1 eye. Patients in the model had a particular therapy until their HbA_1c level reached a specific level (7.5%), at which point they were started on insulin. For patients on dual or triple oral antidiabetic therapy, the next line of treatment was add-on to neutral protamine Hagedorn (NPH) insulin. For patients already on insulin, rescue insulin with glargine was added. The model assumed that patients remained on rescue insulin until they reached the time horizon or died. The change in treatment was applied in 2 other situations: primary failure (that, is lack of efficacy during the first treatment cycle) and in patients with adverse events leading to discontinuation. In these scenarios, patients switched to another therapy of the same line.

3.26   Treatment effectiveness was modelled as the impact of treatment on HbA_1c levels, systolic blood pressure and BMI, and each treatment was associated with an initial effect upon each of these. Lipid ratios, which were also a factor in the UKPDS equations, were assumed to remain constant. With each new treatment combination, changes in HbA_1c and systolic blood pressure followed 3 stages. Firstly, there was a drop in the levels of the risk factors during the first cycle after starting each treatment. This effect was maintained for a period of time (assumed to be 1 year in the base case). Lastly, after this maintenance period, the levels of the risk factors increased based on the UKPDS risk equations.

3.27   To model the treatment effect on weight change, it was assumed that the weight change would happen gradually (distributed equally in each cycle) as long as the patient continued to have the same treatment. The weight was assumed to be maintained over 6 months after the full weight change had been achieved. Whenever a patient switched to a different treatment, it was assumed that the weight at the beginning of the new treatment would be equal to their baseline weight plus the natural weight gain (calculated as 0.1 kg multiplied by the number of years since treatment initiation). The impact on weight of previous treatments was not taken into account.

3.28   Treatment-related adverse events included in the model were hypoglycaemic events (severe and non-severe), urinary tract infections and genital infections. Hypoglycaemia could happen throughout the treatment duration, whereas urinary tract infections and genital infections were assumed to happen only in the first cycle after starting treatment.

3.29   In each cycle patients were at risk of dying as a result of diabetes or other causes. The risk of event-related and diabetes-related mortality followed the UKPDS equations and was dependent on previous complications. Death from other causes also followed the corresponding UKPDS risk equation, but was not influenced by other diabetes-related complications.

3.30   To model the clinical effectiveness, data derived from the company’s network meta-analyses were used in the model most of the time. Results at week 24 from the network meta-analyses were used for the base-case analysis rather than the results at week 52, which were used in a sensitivity analysis. When insulin was added on to existing treatments, the efficacy estimates from an observation study by Khunti et al. were used to model the impact.

3.31   Quality-of-life values were attached to the health states of the model, these values being largely drawn from UKPDS publications. Utility decrements associated with adverse events were taken from Dapagliflozin in combination therapy for treating type 2 diabetes (NICE technology appraisal guidance 288), whereas values for BMI changes were taken from a study by Bagust and Beale (2005). The utility decrement for treatment-related adverse events was applied once per event (in a single cycle), and decrements due to complications were applied for the rest of the time horizon after that event. For a patient with multiple complications, it was assumed that multiple decrements had an additive effect. For weight changes, it was assumed that weight loss did not affect utility but that weight gain would decrease utility. This disutility was applied whenever the total weight gain was higher than the baseline weight of the patient as a result of a treatment-related weight gain. No disutility was applied for the assumed natural increase in weight.

3.32   The company stated that NHS reference costs for the management of long-term conditions were inappropriate for modelling, because they cover a number of different and potentially irrelevant conditions that may not represent the true cost of diabetes management. Therefore, the company sourced the relevant costs of managing complications and adverse events from the published studies (mainly from UKPDS) and previous NICE appraisals, before inflating them to 2013 prices using the hospital and community health services pay and price inflation. No cost was allocated to weight gain because no reliable data were identified. The medication costs were based on British National Formulary (BNF) 66 and the NHS drug tariff. The cost of insulin treatment was based on the average units of insulin used, plus costs of insulin pens, needles and blood sugar test strips .

Company's base-case results

3.33   The company’s submission presented fully incremental analyses of empagliflozin in the following regimens:

• Dual therapy with metformin, comparing empagliflozin, canagliflozin, dapagliflozin and sitagliptin.
• Triple therapy with metformin and a sulfonylurea (glimepiride), comparing empagliflozin, canagliflozin, and sitagliptin.
• Triple therapy with metformin and a thiazolidinedione (pioglitazone), comparing empagliflozin, canagliflozin and sitagliptin.
• As an add-on treatment to insulin (with or without other anti-hyperglycaemic agents), comparing empagliflozin, canagliflozin, dapagliflozin and sitagliptin.

3.34   The base-case analyses showed that there were minimal differences between the treatments compared in terms of total quality-adjusted life years (QALYs) accumulated and life time treatment costs, across all background treatments and all combinations. The incremental QALYs gained ranged between 0.004 and 0.021 and the incremental costs ranged between £26 and £679. The company stated that these differences were not meaningful, highlighting that they had been estimated over a 40‑year time horizon. The results are detailed in table 2.

Table 2 Base-case ICERs in the company's analysis

Intervention	Cost (£)	Incremental cost (£)	QALYs	Incremental QALYs	ICER (£/QALY)
Dual therapy (on background metformin)
Sitagliptin 100 mg	32,046	–	7.425	–	–
Dapagliflozin 10 mg	32,179	133	7.404	−0.021	Dominated by sitagliptin 100 mg
Canagliflozin 100 mg	32,300	255	7.415	−0.01	Dominated by sitagliptin 100 mg
Empagliflozin 25 mg	32,353	307	7.433	0.008	38,425
Empagliflozin 10 mg	32,654	301	7.424	−0.009	Dominated by empagliflozin 25 mg
Canagliflozin 300 mg	32,737	384	7.418	−0.015	Dominated by empagliflozin 25 mg
Triple therapy (on background metformin plus a sulfonylurea)
Canagliflozin 100 mg	31,217	–	6.98	–	–
Sitagliptin 100 mg	31,365	148	6.959	−0.021	Dominated by canagliflozin 100 mg
Empagliflozin 10 mg	31,409	192	6.991	0.011	17,445
Empagliflozin 25 mg	31,557	148	6.978	−0.013	Dominated by empagliflozin 10 mg
Canagliflozin 300 mg	32,087	679	6.976	−0.015	Dominated by empagliflozin 10 mg
Triple therapy (on background metformin plus a thiazolidinedione)
Sitagliptin 100 mg	31,303	–	6.967	–	–
Canagliflozin 100 mg	31,329	26	6.983	0.016	1,644
Empagliflozin 25 mg	31,486	157	6.999	0.016	9,806
Canagliflozin 300 mg	31,866	380	6.978	−0.021	Dominated by empagliflozin 25 mg
Empagliflozin 10 mg	31,869	383	6.996	−0.003	Dominated by empagliflozin 25 mg
In combination with insulin
Canagliflozin 100 mg	30,418	–	6.944	–	–
Dapagliflozin 10 mg	30,545	128	6.953	0.009	14,178
Empagliflozin 10 mg	30,564	18	6.947	−0.006	Dominated by dapagliflozin 10 mg
Empagliflozin 25 mg	30,653	108	6.948	−0.005	Dominated by dapagliflozin 10 mg
Sitagliptin 100 mg	30,682	137	6.912	−0.041	Dominated by dapagliflozin 10 mg
Canagliflozin 300 mg	30,842	296	6.957	0.004	74,075
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. Note: a treatment dominates other treatments when it is less expensive and more effective.

         

Company’s sensitivity analyses

3.35   The company did a range of sensitivity analyses that included:

• applying clinical effectiveness results at week 52
• an alternative set of utility values taken from the UK catalogue of utilities
• with and without applying age-related disutility
• assuming a discontinuation rate similar to empagliflozin 10 mg
• varying the adverse events by applying the lowest number observed across treatments
• assuming that BMI changes did not affect the incidence of congestive heart failure or patient disutility due to weight changes
• assuming that weight change would happen over the first cycle and be maintained over 1 year instead of a gradual increase over the treatment period
• assuming that the duration of treatment effect would last for 2 years instead of 1 year
• varying the time horizon from 40 years to 10 years
• assuming different discount rates (0% and 6%) on costs and effects.

All of these sensitivity analyses confirmed no substantial difference between treatments. The differences in costs and QALYs were also inconsequential across the comparison.

Company’s model validation

3.36   The company’s submission also detailed the verification exercises used to check the internal validity of the model. These included checking face validity of the model output after each cycle and ‘extreme’ sensitivity analyses (in which the cost of the drug and other resources, efficacy of the intervention, utility decrement due to complications, probability of adverse events and discount rates were assumed to be 0, and the probability of treatment discontinuation and treatment failure were assumed to be 1). The company did not provide any data but reported that the results were logical, intuitive and confirmed accurate programming of the model.

3.37   To check the validity of the model further, the company used its model to replicate a cost-effectiveness analysis done during the development of Type 2 diabetes (NICE clinical guideline 66), which compared exenatide with NPH insulin as a third-line treatment. The results showed that in the company’s replication of the analysis, both exenatide and NPH insulin had more QALYs and less costs than in the analyses done for the NICE clinical guideline. For example, in the original clinical guideline analysis, patients on exenatide had an average of 8.08 QALYs and an average cost of £29,001 compared with 8.55 QALYs and a cost of £23,938 in the company’s replication. Similarly, patients having NPH insulin had an average of 8.05 QALYs and an average cost of £19,527 in the original clinical guideline analysis compared with 8.45 QALYs and £17,829 in the replicated analysis. This resulted in a more favourable ICER for exenatide compared with NPH insulin according to the company’s replication (£66,325 per QALY gained) than that estimated by the model during the development of NICE clinical guideline 66 (£280,495 per QALY gained). The company speculated that the difference might be because of different assumptions about some baseline characteristics (such as smoking) and different utility decrements applied for hypoglycaemia and nausea.

3.38   As a further validation exercise for its model, the company submitted an economic evaluation of empagliflozin based on the IMS-CORE diabetes model. For this, the company compared both doses of empagliflozin (10 mg and 25 mg) with dapagliflozin 10 mg in dual therapy (plus metformin) as well as an add-on to insulin. It also compared empagliflozin 10 mg with canagliflozin 100 mg and empagliflozin 25 mg with canagliflozin 300 mg in triple therapy (with metformin and a sulfonylurea). The results of these pair-wise analyses showed that the patients in each arm accrued more QALYs and costs than in the company’s model. However, the incremental differences in QALYs and costs between empagliflozin and other SGLT-2 inhibitors were minimal. As a result, the company concluded that the cost effectiveness of empagliflozin could be considered comparable to other SGLT-2 inhibitors.

Evidence Review Group's comments on the company's cost-effectiveness analyses

3.39   The ERG noted that in the model for each simulation, a single random number was used for each of 100 patients simulated together. This random number was used to determine whether an event would happen to the patient or not. Consequently, it meant that patients who had the same baseline characteristics would have the same complications and adverse events, therefore accruing identical costs and QALYs. According to the ERG, for a patient-level simulation model, different random numbers should have been used for each simulated patient. Since the sampling is a key consideration within an individual patient model, the ERG thought that this limitation would invalidate the modelling in the submission.

3.40   The ERG considered that 300 iterations for 100 patients done to generate model results was an unusually low number for both patients and iterations. The ERG was concerned whether the results obtained by such a low number of simulations would produce robust results given the limitations in the random sampling method. The ERG pointed out that the company’s modelling of HbA_1c, systolic blood pressure and lipid ratios was not in line with the UKPDS 68 equations as it had stated. The ERG also noted errors in the implementation of utility decrement with the weight changes and adverse effects of the treatment. The ERG also noted that the company’s model only applied half the overall QALY decrements associated with adverse events and diabetes complications in its calculation of the total QALYs. The ERG stated that these discrepancies would largely invalidate the results of the company’s model. The ERG identified  some other minor flaws in the company’s model (such as rare occurrence of some patients appearing to die twice).

3.41   Full details of all the evidence are in the evaluation report.

4   Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of empagliflozin, having considered evidence on the nature of type 2 diabetes and the value placed on the benefits of empagliflozin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1   The Committee discussed the clinical treatment pathway for type 2 diabetes. It heard from the clinical specialists that although focused on reducing glycated haemoglobin (HbA1c) without weight gain or hypoglycaemia, treatment for type 2 diabetes is individualised for each patient. This results in some variation in clinical practice. However, current UK practice broadly follows Type 2 diabetes: The management of type 2 diabetes (NICE clinical guideline 87), which recommends a stepwise approach that includes using diet and exercise, various antidiabetic drugs and insulin. The Committee noted that each of the existing antidiabetic therapies had various advantages and disadvantages affecting their suitability for patients and that many patients do not achieve the target HbA1c levels with the existing therapies. The Committee heard from the clinical specialists that empagliflozin would be most valuable for overweight patients with inadequate glycaemic control, who have good renal function and who are not susceptible to genitourinary infections. The Committee understood that a new treatment providing another option would be valued by clinicians.

4.2   The Committee discussed the most likely place for empagliflozin in the treatment pathway, and which treatments in the NICE scope were the key comparators. The Committee noted that many combinations of dual and triple therapy specified in the final scope had not been included in the company's submission, such as empagliflozin plus a sulfonylurea as dual therapy. The Committee heard from the clinical specialists that there may be a small group of people for whom metformin is unsuitable because of intolerance or undesirable effects like weight gain. In these people, empagliflozin plus a sulfonylurea could be used as dual therapy. The Committee also heard from the clinical specialists that empagliflozin could be used as part of dual therapy plus metformin, if sulfonylureas are not suitable due to a perceived risk of hypoglycaemia. The clinical specialists noted that use of thiazolidinediones is decreasing because of safety concerns, particularly increased risk of bladder cancer. The Committee heard from the clinical specialists that even though there may be a place for empagliflozin as part of dual therapy, it is more likely to be used as part of triple therapy. The Committee noted that the company's submission only included dipeptidyl peptidase-4 (DPP-4) inhibitors and other sodium-glucose cotransporter-2 (SGLT-2) inhibitors as the comparators of empagliflozin. The Committee heard from the company that the combinations of dual and triple therapy and the comparators included in its submission were informed by the conclusions made during previous SGLT-2 inhibitors appraisals, specifically Dapagliflozin in combination therapy for treating type 2 diabetes (NICE technology appraisal guidance 288) and Canagliflozin in combination therapy for treating type 2 diabetes (NICE technology appraisal guidance 315). The Committee was persuaded that the combinations and comparators outlined in the company's submission were appropriate for its decision-making.

Clinical effectiveness

4.3   The Committee considered the evidence on the clinical effectiveness of empagliflozin compared with other antidiabetic treatments and noted that most of the trials compared empagliflozin with placebo. The Committee noted the Evidence Review Group (ERG)'s comment that the trials were generally of good methodological quality and that demographic characteristics were well balanced. The Committee noted that in general, compared with placebo, empagliflozin was proven to be effective in reducing HbA1c, body weight and systolic blood pressure in dual therapy (plus metformin), in triple therapy (plus metformin and a sulfonylurea or a thiazolidinedione) or as an add-on to insulin. The Committee also heard from the clinical specialists about their anecdotal experience of empagliflozin for treating type 2 diabetes in the trials. The clinical specialists were satisfied with their experience so far and recalled that they had not witnessed any immediate safety concerns. They also stated that their patients achieved better glycaemic control and weight reduction than had been suggested by the results in the trials. The clinical specialists also suggested that although the trials did not show any improvement in quality-of-life scores, patients generally valued the weight reduction achieved by empagliflozin. However, the clinical specialists also stressed that they had limited experience, having treated only a small number of people with empagliflozin. The Committee concluded that empagliflozin in combination with other antidiabetic agents is proven to be an effective treatment compared with placebo for type 2 diabetes.

4.4   The Committee discussed the network meta-analyses which reported the relative effectiveness of empagliflozin with the relevant comparators in the absence of head-to-head trials. The Committee noted the results of the network meta-analyses, which suggested that empagliflozin could be considered to have similar clinical effectiveness  to canagliflozin, dapagliflozin and sitagliptin when used:

• in dual therapy plus metformin or a thiazolidinedione
• in triple therapy plus metformin and a sulfonylurea
• in triple therapy plus metformin and a thiazolidinedione
• as an add-on treatment to insulin.

The Committee noted the ERG's concerns with the way in which the network meta-analyses were done and reported. The Committee was reassured by the company, which stated that it had corrected many of the errors identified by the ERG and it did not have any substantial effect on the results and overall conclusion that the clinical effects were similar between empagliflozin, canagliflozin, dapagliflozin and sitagliptin. The Committee heard from the ERG that results of an independent unpublished network meta-analysis, comparing SGLT-2 inhibitors as dual therapy plus metformin, supports the conclusion of similar clinical effectiveness among SGLT-2 inhibitors. The Committee concluded on the basis of the network meta-analyses that empagliflozin as part of dual therapy, triple therapy and as an add-on to insulin appeared to provide comparable glycaemic control to both other SGLT-2 inhibitors and DPP-4 inhibitors.

4.5   The Committee discussed the adverse events associated with empagliflozin. It noted that common adverse events associated with SGLT-2 inhibitors include urinary tract and genital infections, and that these are more common in women than in men. The Committee heard from the clinical specialists that in their experience, in patients treated with empagliflozin the incidence of these infections was low. The Committee was aware that the European public assessment report for empagliflozin reported that cardiovascular adverse events were lower for empagliflozin compared with placebo, even though the follow-up was short and the analysis included a small number of people. The Committee was concerned about the lack of long-term efficacy and safety data and heard from the clinical specialists that like other SGLT-2 inhibitors, empagliflozin therapy would be stopped in patients in whom no adequate clinical response was seen within 6 months. The Committee concluded that the short-term adverse events of empagliflozin seemed similar to those of other SGLT-2 inhibitors. The Committee also noted that like other SGLT-2 inhibitors, long-term outcomes of empagliflozin treatment were uncertain because of a lack of data.

4.6   The Committee then discussed the economic model submitted by the company, noting that it was a new model developed for this appraisal. The Committee noted the ERG's comments regarding its quality and robustness, with the ERG highlighting several errors in the construct of the model which would invalidate any results (see sections 3.39-3.40). The Committee was aware that the company had acknowledged most of the errors identified by the ERG. It asked the company why it had preferred to develop a new model when commercially available diabetes models were available. The company informed the Committee that it had aimed to develop a fully transparent model which could be adapted as per the needs of the submission. The company also acknowledged that, on reflection, using a model that was commercially available or had been used in a previous technology appraisal would have been a better approach. The Committee also discussed 1 of the model validation exercises carried out by the company. It noted that replicating an analysis carried out for Type 2 diabetes (NICE clinical guideline 66) comparing exenatide with neutral protamine Hagedorn (NPH) insulin using the company's model, showed that both treatments accrued more quality-adjusted life years (QALYs) and less costs than in the previous analysis. The incremental cost-effectiveness ratio (ICER) for exenatide compared with NPH insulin was much lower in the company's model than in the original model (see section 3.37). The Committee concluded that the company's model was inherently flawed and so its results could not be considered reliable for making recommendations.

4.7   Having agreed that the company's model and its results were unreliable, the Committee discussed whether there were any other available robust analyses of the cost effectiveness of empagliflozin. The Committee noted that as a model validation exercise, the company used a commercially available diabetes model, using where possible the same input parameters as the model that it had developed (see section 3.38). The Committee noted that not all relevant combinations and comparators of empagliflozin listed in the company's decision problem were included in these analyses. It also noted that in the validation exercise, empagliflozin was compared with neither sitagliptin nor canagliflozin in dual therapy or as an add-on to insulin therapy. The Committee agreed that it would have preferred to see all analyses in the company's submission comparing both doses of empagliflozin with sitagliptin (a DPP-4 inhibitor) and other SGLT-2 inhibitors (dapagliflozin and both doses ofcanagliflozin) in a fully incremental way in accordance with the NICE reference case, replicated in a validated model. The Committee was also concerned that the ERG had not been able to review the validation exercise in detail in the time available to prepare its critique of the company's submission. The Committee heard from the ERG that the diabetes model used for this validation exercise is considered to be robust and validated model. The Committee was aware of the complexities of economic modelling in diabetes, but reiterated that it could not make recommendations without being presented with a robust estimate of cost effectiveness. The Committee agreed that to inform its decision-making, it would like to see the estimation of empagliflozin's cost effectiveness compared with that of all relevant comparators, using a more reliable model such as that used for the validation exercise. It noted that it would also like to see the combined effect of any uncertainties associated with the parameters assessed together in probabilistic sensitivity analyses. The Committee concluded that it had not been presented with enough information to make recommendations for empagliflozin for treating type 2 diabetes, and that it needed additional analyses to inform its decision-making. Therefore, the Committee was minded not to recommend empagliflozin in combination with oral antidiabetic agents with or without insulin for treating type 2 diabetes. The Committee requested further analyses from the company, which should be made available for the second Appraisal Committee meeting, and which should include:

• revised estimation of the incremental cost-effectiveness ratios of empagliflozin using a validated economic model, informed by the corrected results of network meta-analyses and compared with relevant comparators (SGLT-2 inhibitors and DPP-4 inhibitors)
• sensitivity analyses should also include probabilistic exploration of parameter uncertainty.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Empagliflozin combination therapy for treating type 2 diabetes		Section
Key conclusion
The Committee is minded not to recommend empagliflozin within its marketing authorisation as combination therapy with or without insulin for treating type 2 diabetes. The Committee recommends that NICE requests further analyses from the company, which should be made available for the second Appraisal Committee meeting, and should include: ·         revised estimation of the incremental cost-effectiveness ratios of empagliflozin using a validated economic model, informed by the corrected results of network meta-analyses and compared with relevant comparators (sodium‑glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors) ·         sensitivity analyses which should also include probabilistic exploration of parameter uncertainty. The Committee concluded that the company’s model was inherently flawed and so its results could not be considered reliable for making recommendations.			1.1 1.2 4.6
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the clinical specialists that although focused on reducing glycated haemoglobin (HbA1c) without weight gain or hypoglycaemia, treatment for type 2 diabetes is individualised for each patient. This results in some variation in clinical practice. However, current UK practice broadly follows Type 2 diabetes: The management of type 2 diabetes (NICE clinical guideline 87), which recommends a stepwise approach that includes using diet and exercise, various antidiabetic drugs and insulin.   The Committee noted that each of the existing antidiabetic therapies had various advantages and disadvantages affecting their suitability for patients, and that many patients do not achieve the target HbA1c levels with existing therapies.	4.1
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from the clinical specialists that empagliflozin would be most valuable for overweight patients with inadequate glycaemic control, who have good renal function and who are not susceptible to genitourinary infections. The company did not make any claim for innovation.	4.2
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialists that even though there may be a place for empagliflozin as part of dual therapy, it is more likely to be used as part of triple therapy.	4.2
Adverse reactions		The Committee noted that common adverse events associated with SGLT-2 inhibitors include urinary tract and genital infections, and that these are more common in women than in men. The Committee concluded that the short-term adverse events of empagliflozin seemed similar to those of other SGLT-2 inhibitors, and that long-term effects were uncertain because of a lack of data.	4.5
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted the ERG’s comment that the empagliflozin trials were generally of good methodological quality and that demographic characteristics were well balanced. The Committee discussed the network meta-analyses which reported the relative effectiveness of empagliflozin with the relevant comparators in the absence of head-to-head trials. The Committee noted the ERG’s concerns with the way in which the network meta-analyses were done and reported.	4.3 4.4
Relevance to general clinical practice in the NHS		The Committee heard from the clinical specialists about their anecdotal experience of empagliflozin for treating type 2 diabetes in the trials. The clinical specialists were satisfied with their experience so far and recalled that they had not witnessed any immediate safety concerns. They also stated that their patients achieved better glycaemic control and weight reduction than had been suggested by the results in the trials. The clinical specialists also suggested that although the trials did not show any improvement in quality-of-life scores, patients generally valued the weight reduction achieved by empagliflozin.	4.3
Uncertainties generated by the evidence		The Committee noted that most of the trials compared empagliflozin with placebo and discussed the network meta-analyses which reported the relative effectiveness of empagliflozin with the relevant comparators in the absence of head-to-head trials. The Committee noted the ERG’s concerns with the way in which the network meta-analyses were done and reported. The Committee was concerned about the lack of long-term efficacy and safety data and heard from the clinical specialists that like other drugs in the same class, empagliflozin would be stopped in patients  in whom  no adequate clinical response was seen within 6 months.	4.3 4.4 4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		On the basis of clinical trial results, the Committee concluded that empagliflozin in combination with other antidiabetic agents is proven to be an effective treatment compared with placebo for type 2 diabetes. The Committee concluded on the basis of the network meta-analyses that empagliflozin as part of dual therapy, triple therapy and as an add-on to insulin appeared to provide comparable glycaemic control to both other SGLT-2 inhibitors and DPP-4 inhibitors.	4.3 4.4
Evidence for cost effectiveness
Availability and nature of evidence		The Committee discussed the economic model submitted by the company, noting that it was a new model developed for this appraisal. The Committee noted the ERG’s comments regarding its quality and robustness, which highlighted several errors in the construct of the model. The Committee was aware that the company had acknowledged most of the errors identified by the ERG.	4.6
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted the ERG’s comments regarding the model’s quality and robustness, with the ERG highlighting several errors in the construct of the model which would invalidate any results. The Committee concluded that the company’s model was inherently flawed and so its results could not be considered reliable for making recommendations.	4.6
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		Not applicable.
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		There were no specific Committee considerations on the key drivers of cost effectiveness since the Committee concluded that the company’s model was inherently flawed and so its results could not be considered reliable for making recommendations.	4.6
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that the company’s model was inherently flawed and so its results could not be considered reliable for making recommendations.	4.6
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		No issues relating to equality considerations were raised in the submissions, or in the Committee meeting.

 

5  Implementation

5.1   NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6   Related NICE guidance

Details are correct at the time of consultation and will be removed when the final guidance is published. Further information is available on the NICE website.

Published

• Canagliflozin in combination therapy for treating type 2 diabetes. NICE technology appraisal guidance 315 (2014).
• Dapagliflozin in combination therapy for treating type 2 diabetes. NICE technology appraisal guidance 288 (2013).
• Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes. NICE technology appraisal guidance 248 (2012).
• Liraglutide for the treatment of type 2 diabetes. NICE technology appraisal guidance 203 (2010).
• Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes (partial update of CG66). NICE clinical guideline 87 (2009)
• Type 2 diabetes: the management of type 2 diabetes (partially updated by CG87). NICE clinical guideline 66 (2008).
• Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. NICE clinical guideline 63 (2008).
• Continuous subcutaneous insulin infusion for the treatment of diabetes (review). NICE technology appraisal guidance 151 (2008).
• Type 2 diabetes: prevention and management of foot problems. NICE clinical guideline 10 (2004).

Under development

• Type 2 diabetes in adults: management of type 2 diabetes in adults. NICE clinical guideline, publication expected August 2015.
• Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes. NICE technology appraisal guidance, publication expected January 2016

NICE pathways

• There is a NICE pathway on diabetes.

7   Proposed date for review of guidance

7.1   NICE proposes that the guidance on this technology is considered for review by the Guidance Executive 3 years after publication of the guidance. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Iain Squire
Chair, Appraisal Committee
August 2014

8   Appraisal Committee members, guideline representatives and NICE project team

Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital, London

Professor Iain Squire (Vice-Chair)
Consultant Physician, University Hospitals of Leicester

Professor Thanos Athanasiou
Professor of Cardiovascular Sciences and Cardiac Surgery, Imperial College London; Consultant Cardiothoracic Surgeon, Imperial College Healthcare NHS Trust

Dr Graham Ash
Consultant in General Adult Psychiatry, Lancashire Care NHS Foundation Trust

Dr Gerardine Bryant
GP, Swadlincote, Derbyshire

Dr Simon Bond
Senior Statistician, Cambridge Clinical Trials Unit

Dr Andrew England
Senior Lecturer, Directorate of Radiography, University of Salford

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital, Bristol

Dr Sharon Saint Lamont
Head of Clinical Quality, NHS England (North)

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Dr Anne McCune
Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

Professor John McMurray
Professor of Medical Cardiology, University of Glasgow

Sarah Parry
CNS Paediatric Pain Management, Bristol Royal Hospital for Children

Pamela Rees
Lay member

Dr Ann Richardson
Lay member

Stephen Sharp
Senior Statistician, University of Cambridge MRC Epidemiology Unit

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital

Dr Peter Sims
GP, Devon

David Thomson
Lay member

NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Dr Anwar Jilani
Technical Lead

Dr Sally Doss
Technical Adviser

Bijal Joshi
Project Manager

9   Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Warwick Evidence:

• Shyangdan D, Jacob R, Connock M et al. Empagliflozin combination therapy for treating type 2 diabetes:A Single Technology Appraisal. July 2014

 

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I. Company:

• Boehringer Ingelheim

II. Professional/specialist and patient/carer groups:

• Association of British Clinical Diabetologists
• Black and Ethnic Minority Diabetes Association
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association

III. Other consultees:

• Department of Health
• NHS England
• Welsh Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal):

• Astra Zeneca
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Janssen
• Merck Sharp and Dohme
• Novo Nordisk
• National Institute for Health Research Health Technology Assessment Programme
• Warwick Evidence

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on empagliflozin by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Peter Winocour, Consultant Diabetologist and Clinical Director, nominated by Association of British Clinical Diabetologists and Royal College of Physicians – clinical specialist
• Dr T Sathyapalan, Reader/Honorary Consultant Diabetologist, nominated by Association of British Clinical Diabetologists and Royal College of Physicians - clinical specialist
• Aderonki Kuti, Chief Executive Officer, nominated by Black Ethnic Minority Diabetes Association

E. Representatives from the following company attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

•  Boehringer Ingelheim