4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ticagrelor, having considered evidence on the nature of ACS and the value placed on the benefits of ticagrelor by people with these conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the clinical management of ACS. It heard from the clinical specialists that, in the UK, treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment. The Committee heard that the duration of treatment of clopidogrel does not vary whether a stent is bare-metal or drug-eluting, because all people with ACS who undergo PCI, in the acute setting, are treated with clopidogrel plus aspirin for 12 months. The Committee heard that in UK clinical practice people with NSTEMI are offered treatments depending on their GRACE or TIMI score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin. The Committee heard from the clinical specialists that in the UK most people with NSTEMI undergo PCI. The Committee understood that of people in the UK with ACS, few have unstable angina and often do not need revascularisation, but do receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo CABG and that approximately 10% of patients with NSTEMI undergo CABG.

Clinical effectiveness

4.3 The Committee considered the evidence for the clinical effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The Committee noted that ticagrelor plus aspirin reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel plus aspirin. The Committee also noted that if the components of the primary end point were considered individually, the reductions in myocardial infarction and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor plus aspirin group. The Committee also noted the non-statistically significant increase in the incidence of stroke, in particular haemorrhagic stroke, in patients randomised to the ticagrelor group. The Committee considered the clinical evidence for ticagrelor plus aspirin compared with clopidogrel plus aspirin in the subgroups of patients that were specified in the scope (STEMI, NSTEMI and unstable angina) and noted that the test for interaction showed no statistical difference between the groups (p = 0.41), interpreting this as no difference in the effectiveness between treatments by clinical presentation of ACS. The Committee noted that the manufacturer had performed a large substudy of quality of life based on EQ-5D scores, which indicated no difference in the quality of life between people taking ticagrelor plus aspirin and those taking clopidogrel plus aspirin.

4.4 The Committee heard from the clinical specialists that in general the trial was representative of the population in the UK, although the trial had a younger population and a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had accounted for age in its analysis. The Committee noted comments from consultees and commentators questioning the generalisability of the PLATO trial to UK clinical practice because most of the patients presenting with ACS in the UK would receive medical therapy only whereas 21% of patients in the PLATO trial received medical therapy only. However, the Committee noted the clinical specialists' testimonies that most STEMI and NSTEMI patients would receive PCI. The Committee was also aware that results of the PLATO study showed no statistically significant difference in effectiveness between the patients whose condition was managed medically or otherwise. The Committee concluded that the trial was broadly reflective of clinical practice in the UK.

4.5 The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation, and that of those randomised to clopidogrel, only approximately one fifth received a loading dose in the range (600–675 mg) recommended in the UK (600 mg). The Committee also noted that not all patients in the PLATO trial received treatment for 12 months and that the median duration of treatment was 9 months. The Committee heard that the results presented included those censored before 12 months. The Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated as early as 1 month and up to 1 year and, therefore, concluded that neither the difference in loading doses of clopidogrel nor censoring was likely to have substantially biased the results.

4.6 The Committee understood that ticagrelor is administered twice a day compared with once a day with clopidogrel and heard from the patient experts that, in practice, people may be less likely to take drugs twice a day. The Committee noted that no clear differences had been established on adherence between once-a-day clopidogrel and twice-a-day ticagrelor. The Committee noted comments from consultees and commentators that, particularly with a gastrointestinal bleed, the fast offset (time taken for ticagrelor to become inactive after it is stopped) could put a patient at increased risk of myocardial infarction and stroke more quickly than had the patient been taking clopidogrel, and with insufficient time to consult a cardiologist. However, the Committee heard from the manufacturer that missing a dose of ticagrelor would not result in a lower level of platelet activation than if the patient were treated with clopidogrel without missing a dose. The Committee heard that when a CABG is planned, the marketing authorisation recommends stopping ticagrelor 7 days before the procedure, suggesting that the offset is not as fast as had been suggested in the consultation comments. The Committee also noted comments from consultees and commentators that treatment with ticagrelor should be limited to people who clinicians have counselled on the importance of adherence. The Committee heard from the clinical specialists that people taking clopidogrel or ticagrelor would usually receive information to ensure that they understand why adherence is important and why stopping treatment early might increase the risk of recurrent cardiovascular disease. Therefore, the Committee agreed that advice on adherence should not explicitly be factored into the recommendations. Lastly, the Committee noted that most patients with cardiovascular disease take drugs twice a day, including statins in the evening. The Committee concluded that in the 'real world' setting, the need to take medication twice a day rather than once a day would be unlikely to substantially reduce the effectiveness of ticagrelor plus aspirin relative to clopidogrel plus aspirin.

4.7 The Committee discussed the concerns about safety and adverse effects associated with ticagrelor. The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increases in serum uric acid and increases in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group, and noted that patients randomised to ticagrelor were more likely to discontinue the study drug because of adverse reactions. The Committee heard from the patient experts that dyspnoea frustrated patients with ACS and the clinical specialists stated that a patient randomised to ticagrelor was nine times as likely to discontinue the study because of dyspnoea as a patient randomised to clopidogrel, but that the absolute risk, at less than 1%, was small. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted no statistically significant difference in the primary safety end point of major bleeding between ticagrelor plus aspirin and clopidogrel plus aspirin but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.

4.8 The Committee discussed whether ticagrelor plus aspirin would be more or less effective in any subgroups including patients with STEMI, NSTEMI or unstable angina. The Committee noted that several additional subgroups were presented in the trial. The Committee noted that among those defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared with clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted the comment from a consultee saying that patients with unstable angina are unlikely to benefit from ticagrelor because subgroup analysis shows benefit only for patients whose blood tests following the index event were positive for troponin. The Committee noted, however, that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for interaction 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease. Therefore, the Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter the statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.

4.9 The Committee was aware of comments from consultees and commentators that the estimate of total mortality remained 'exploratory'. This was because the analysis plan for PLATO stated that secondary end points should be tested individually in a pre-specified order, so mortality should not have been included because it followed the non-statistically significant result for stroke. The Committee was aware that the result for the association between ticagrelor and total mortality, while exploratory, had a HR of 0.78 and a 95% CI of 0.69 to 0.89, so was likely to reflect a real decrease in total mortality associated with ticagrelor plus aspirin.

4.10 The Committee noted the concerns around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin highlighted in the manufacturer's submission and reiterated by the ERG. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.

Cost effectiveness

4.11 The Committee considered the estimates of cost effectiveness presented in the manufacturer's submission and noted that all ICERs for ticagrelor were below £5400 for the whole population in which ticagrelor is licensed and the subgroups. The Committee was aware of the concerns raised by the ERG around the structure of the model adopted in the manufacturer's submission, and agreed that the assumption that patients could not experience multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event after the index event, and had accounted for the increased risk of a cardiovascular event associated with having had prior events, then the ICERs for ticagrelor compared with clopidogrel would be lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event. The Committee was aware of the ERG's concerns over the method used to adjust for age, but agreed that this would not result in major changes to the ICERs. The Committee also noted that it would have been more appropriate to incorporate a utility value that reflected clinical practice rather than modelling the average utility score, but acknowledged that this too was unlikely to have a large impact on the ICERs. The Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.

4.12 The Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms. The Committee accepted the ERG's adjustments to the manufacturer's model and noted the resulting estimates of cost effectiveness. The Committee agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources and therefore ticagrelor plus low-dose aspirin should be recommended as a treatment option for up to 12 months in adults with ACS. However the Committee agreed that the patient populations for STEMI and unstable angina needed to be further specified.

4.13 The Committee noted that the inclusion criteria in the PLATO trial for patients with STEMI, defined as ST elevation or new left bundle branch block on electrocardiogram, included the 'intention to perform primary PCI'. The Committee therefore agreed that only patients with STEMI that cardiologists intend to treat with primary PCI should be treated with ticagrelor. The Committee heard that there is a spectrum of severity with respect to unstable angina. The Committee was aware that in clinical practice in the UK a diagnosis of unstable angina could be made using less stringent criteria than those defined in the PLATO trial. The Committee agreed that only patients with unstable angina aligned with the definition in the PLATO trial should be treated with ticagrelor. The Committee noted that the definition of unstable angina in the PLATO trial was that patients were hospitalised and had to have ST-segment changes on electrocardiography indicating ischemia, and that patients had at least one of the following characteristics: age 60 years or older; previous myocardial infarction or CABG; coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke, transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m2 of body-surface area. The Committee was aware that it may be necessary to start treatment with ticagrelor immediately when a patient presents with symptoms. However, the Committee was concerned that a wrong diagnosis of unstable angina could result in the patient unnecessarily taking ticagrelor. The Committee therefore agreed that it would be appropriate to specify that before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.

4.14 The Committee noted the comments from consultees and commentators about whether 'lowest risk' patients (that is, patients who have a 6-month mortality of 1.5% or less as defined by the GRACE scoring system) should receive ticagrelor, given that Unstable angina and NSTEMI (NICE clinical guideline 94) stipulates that these patients would not receive clopidogrel because the harms potentially outweigh the benefits. The Committee concluded that, because patients potentially suitable for treatment with ticagrelor with unstable angina must have at least one specific risk factor for myocardial infarction as well as ST-segment changes on electrocardiography, these patients would therefore not be classed as 'lowest risk'.

4.15 The Committee heard from the primary care trust expert that although treatment with ticagrelor relative to clopidogrel appeared cost effective within the range considered to represent good value for money by NICE, the high incidence of ACS in England and Wales means that ticagrelor would substantially impact budgets were it approved for use. The primary care trust expert noted that this would invariably lead to reduced spending elsewhere for health, which would include cardiology services. The Committee noted further comments received from consultees that affordability was an issue that NHS commissioners needed to consider 'very seriously'. Although the Committee agreed that that budget impact would be substantial, it was possible that any services displaced might be less cost effective than ticagrelor relative to clopidogrel. Moreover, the Committee noted that NICE's current guide to the methods of technology appraisal states that budget impact and affordability are not relevant to its decision making.

Summary of Appraisal Committee's key conclusions

TA236 (STA)

Ticagrelor for the treatment of acute coronary syndromes

FAD section

Key conclusion

Ticagrelor in combination with low-dose aspirin is recommended for up to 12 months as a treatment option in adults with acute coronary syndromes (ACS) that is, people:

• with ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or

• with non-ST-segment-elevation myocardial infarction (NSTEMI) or

• admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.

1.1

The Committee noted that the incremental cost-effectiveness ratios (ICERs) produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.

4.12

Current practice

Clinical need of patients, including the availability of alternative treatments

Treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment.

People with NSTEMI are offered treatments depending on their Global Registry of Acute Coronary Events (GRACE) or Thrombolysis in Myocardial Infarction (TIMI) score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin.

People with unstable angina often do not need revascularisation, but receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo coronary artery bypass grafting (CABG) and that approximately 10% of patients with NSTEMI undergo CABG.

4.2

The technology

Proposed benefits of the technology

Ticagrelor is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease.

2.1

How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?

No specific claim of innovation was made.

What is the position of the treatment in the pathway of care for the condition?

Ticagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only or may also undergo revascularisation with PCI or CABG.

2.1

Adverse events

The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increase in serum uric acid and increase in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group.

3.5

The Committee noted that there was no statistically significant difference in the primary safety end point of major bleeding between ticagrelor and clopidogrel but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.

4.7

Evidence for clinical effectiveness

Availability, nature and quality of evidence

The manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The PLATO trial was an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study.

3.1

The manufacturer had performed a large quality of life substudy based on EQ-5D scores.

4.3

There was no direct comparison of ticagrelor and prasugrel and there were concerns around the indirect comparison of ticagrelor and prasugrel.

4.10

Relevance to general clinical practice in the NHS

The Committee heard from the clinical specialists that overall the trial was representative of the population in the UK, although it was noted that the population in the trial was younger and had a higher proportion of men than the population with ACS in the UK.

4.4

The standard loading dose of clopidogrel in the UK is 600 mg but only a fifth of patients in the PLATO trial had received this dose. However, the Committee concluded that the trial was broadly reflective of clinical practice in the UK.

4.5

Uncertainties generated by the evidence

The population in the trial was younger and had a higher proportion of men than people with ACS in the UK, but the manufacturer had taken account of this in its economic modelling. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose.

4.4

The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation. However, the Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated prior to and up to 1 year and, therefore, concluded that the difference in loading doses of clopidogrel was unlikely to have substantially biased the results.

4.5

The Committee noted the concerns of the manufacturer and ERG around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.

4.10

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?

The Committee noted that among those subgroups defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared to clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a real difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for heterogeneity 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease, that is, in people who had not experienced an acute myocardial infarction. The Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.

4.8

Estimate of the size of the clinical effectiveness including strength of supporting evidence

The Committee noted that ticagrelor reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel.

The Committee also noted that if the components of the primary end point were considered individually, ticagrelor plus aspirin statistically significantly reduced myocardial infarctions by 16% and death from vascular causes by 21% compared with clopidogrel plus aspirin. Treatment with ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12 months compared with clopidogrel plus aspirin.

3.3, 4.3

Evidence for cost effectiveness

Availability and nature of evidence

The manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to the lifetime horizon (40 years), and to incorporate major clinical events and resource use.

3.9

For the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.

3.8

Uncertainties around and plausibility of assumptions and inputs in the economic model

The Committee agreed that the assumption that patients could not have multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event and an increased risk of further events associated with a first or subsequent event, then the ICERs for ticagrelor compared with clopidogrel would have been lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event.

The Committee was aware of the ERG's concerns over the method used to adjust for age but agreed that this would not result in major changes to the ICERs.

The Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.

The Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms, and accepted the ERG's adjustments to the manufacturer's model.

4.11, 4.12

Incorporation of health-related quality of life benefits and utility values

The manufacturer used the 12-month cohort in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period.

3.13

The Committee noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this was unlikely to have a large impact on the ICERs.

4.11

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 identified.

Are there specific groups of people for whom the technology is particularly cost effective?

See section on subgroups above.

4.8

What are the key drivers of cost effectiveness?

Only the change to the costs of the health state in which a patient does not experience an additional cardiovascular event impacted substantially on the results. When the cost of the 'no further event' health state for ticagrelor plus aspirin was set to its lowest, ticagrelor plus aspirin dominated clopidogrel plus aspirin (that is, ticagrelor plus aspirin was more effective and less expensive than clopidogrel plus aspirin), whereas when the cost of the clopidogrel plus aspirin 'no further event' health state was set to its lowest, the ICER was £21,000 per quality-adjusted life year (QALY) gained. Changes in all other parameters did not increase the ICER beyond £7620 per QALY gained.

3.16

Results using time horizons of 1 year, 5 years, 10 years and 20 years were also presented: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained.

3.15

Most likely cost-effectiveness estimate (given as an ICER)

The Committee accepted the ERG's adjustments to the manufacturer's model and agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel.

4.12

Additional factors taken into account

Patient access scheme

Not applicable

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End-of-life considerations

Not applicable

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Equalities considerations, Social value judgements

No equality issues were identified during the scoping process or the appraisal.

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