4 Evidence and interpretation
4.1.1 The systematic review carried out by the Assessment Group (appendix B) identified seven published reports of randomised controlled trials (RCTs) of cinacalcet versus placebo in people with hyperparathyroidism secondary to ESRD who were receiving dialysis. Most of these publications reported on one or more of four RCTs sponsored by the manufacturer of cinacalcet, although three smaller RCTs were also identified. In addition, the manufacturer submitted information on an unpublished study relating to an RCT designed to evaluate optimal levels of concomitant vitamin D and phosphate binders in patients receiving standard care with or without cinacalcet. All studies were designed to assess biochemical endpoints (namely changes in plasma PTH, serum calcium, serum phosphorus and Ca x P). One small study (n = 14) also reported on bone mineral density. Seven of the RCTs had durations of 26 weeks or less, with dose titration phases of between 12 and 16 weeks and efficacy assessment phases of between 6 and 14 weeks. The remaining study was 52 weeks long, with a 24-week dose titration period followed by a 28-week efficacy assessment.
4.1.2 Improvements in mean levels of PTH, calcium, phosphorus and Ca x P observed in the trials were statistically significantly greater in the cinacalcet groups in most of the studies that reported these endpoints. Generally, patients receiving cinacalcet had decreases from baseline for all four measures, with placebo-treated patients experiencing increases or, in some cases, decreases of lower magnitude. However, in two studies that reported changes in serum phosphorus levels (n = 71 and n = 48), differences in changes between the groups were not statistically significant, and in the smaller of these two studies patients receiving placebo had a greater reduction in phosphorus compared with those receiving cinacalcet. However, these two studies were not designed or powered to detect clinically meaningful differences in serum phosphorus.
4.1.3 A pooled analysis of the three largest RCTs (n = 1136) showed that target mean intact PTH levels were reached in 40% of patients randomised to cinacalcet, compared with 5% of patients receiving placebo (p < 0.001). In these studies, a target intact PTH level was defined as lower than 26.5 pmol/litre (250 pg/ml). Similar results were seen in another two studies that measured this endpoint. In these two studies the proportions of patients with target intact PTH levels were 53% versus 6% (n = 48, statistical significance not reported) and 44% versus 20% (n = 71, p = 0.029) for patients receiving cinacalcet and placebo respectively.
4.1.4 Statistically significantly more patients who were treated with cinacalcet had a reduction of at least 30% in mean intact PTH levels compared with those receiving standard care alone in all RCTs that reported this outcome. In the pooled analysis of the three largest studies, 62% of patients treated with cinacalcet had a reduction of at least 30%, versus 11% in the placebo arm (p = 0.029). This endpoint was reported in two other studies, which also favoured cinacalcet over standard care. In these studies the proportions of patients with a reduction of at least 30% in mean intact PTH levels were 38% versus 8% (n = 78, p = 0.001) and 53% versus 23% (n = 71, p = 0.009) for patients receiving cinacalcet and placebo respectively.
4.1.5 A post-hoc analysis of pooled data from four RCTs designed to investigate changes in biochemical markers (n = 1184) assessed the effects of cinacalcet compared with placebo on the clinical outcomes of fracture, cardiovascular hospitalisation, all-cause hospitalisation, parathyroidectomy and mortality. No statistically significant differences were seen in overall mortality or all-cause hospitalisation. However, statistically significant differences were observed in fracture (relative risk [RR] 0.46; 95% confidence interval [95% CI] 0.22–0.95), cardiovascular hospitalisation (RR 0.61; 95% CI 0.43–0.86), and parathyroidectomy (RR 0.07; 95% CI 0.01–0.55) based on follow-up of 6–12 months.
4.1.6 The same analysis also reported combined data on health-related quality of life, based on the SF-36 health survey. At baseline in both treatment groups the scores on the eight domains of the scale were approximately half to one standard deviation below the general population means. For the physical component summary score there was a 0.5-unit improvement in the cinacalcet arms compared with a 0.8-unit decrease in the control arms (p = 0.01); for the bodily pain scale there was a 0.6-unit improvement in the cinacalcet arms compared with a 1.0-unit decrease in the control arms (p = 0.03); and for the general health perception scale there was a 0.2-unit improvement in the cinacalcet arms compared with a 1.0-unit decrease in the control arms (p = 0.02). No statistically significant differences were found for the other domains. The Committee heard from the patient experts that bone pain could result in considerable disability and that a reduction in bone pain was an important benefit of treatment.
4.1.7 The Assessment Group reported subgroup analyses by baseline plasma intact PTH, serum Ca x P, serum calcium, serum phosphorus and dialysis duration for a variety of biochemical endpoints. However, most of these did not indicate statistically significant differences between subgroups. The Assessment Group noted that some results suggested that cinacalcet may be more effective in less advanced disease, but were cautious about interpreting these findings.
4.1.8 The manufacturer's submission reported unpublished results of an open-label post-marketing study (n = 552) that randomised participants to standard care with or without cinacalcet. The primary endpoint was the proportion of patients with a mean plasma intact PTH level of 31.8 pmol/litre (300 pg/ml) or less during a 7-week efficacy phase, following a 16-week titration phase. In contrast to previous trials, this study allowed the adjustment of doses of vitamin D sterols and phosphate binders in accordance with treatment algorithms (in other RCTs, doses were held constant to minimise the potential for confounding). The primary endpoint was reached by 71% of patients in the cinacalcet arm compared with 22% of patients receiving standard care alone (p < 0.001). Although the proportion of patients taking vitamin D sterols increased in both arms (66% to 81% in the standard care arm; 68% to 73% in the cinacalcet arm), the mean relative dose of vitamin D sterol decreased by 22% in the cinacalcet arm, whereas a 3% increase occurred in the standard care arm. The proportions of patients taking phosphate binders in the two groups were similar throughout the study. The proportion of patients taking calcium-containing phosphate binders or calcium supplements remained stable over the study period in the standard care group, and increased in the group of patients receiving cinacalcet.
4.2.1 The systematic review carried out by the Assessment Group did not identify any published cost-effectiveness studies relevant to the scope of this appraisal. An economic model and separate cost–consequence analysis were submitted by the manufacturer of cinacalcet, and the Assessment Group developed its own economic model. Both models were cost–utility analyses comparing cinacalcet in addition to standard care (using vitamin D and phosphate binders) with standard care only in patients with secondary hyperparathyroidism (PTH > 31.6 pmol/litre) who were receiving dialysis. Both analyses adopted the perspective of the NHS, and generally similar cost and resource-use assumptions were used. There were, however, differences between the models in the assumptions driving effectiveness.
4.2.2 The model submitted by the manufacturer incorporated health states reflecting patients' status in relation to adverse events associated with secondary hyperparathyroidism. Clinical events included in the analysis were cardiovascular hospitalisations, fractures (major and minor), parathyroidectomies and death. The effect of cinacalcet on the relative risks for these outcomes was based on the pooled results of four clinical trials. The manufacturer's model resulted in an incremental cost-effectiveness ratio (ICER) of £35,600 per quality-adjusted life year (QALY) gained. Subgroup analyses in patients with moderate (PTH 31.6 to 84.2 pmol/litre) and severe (PTH > 84.2 pmol/litre) secondary hyperparathyroidism resulted in ICERs of £30,400 and £48,300 per QALY gained respectively. Various one-way sensitivity analyses were conducted. The results of these indicated that the ICER was most sensitive to variations in the dose of cinacalcet.
4.2.3 The Assessment Group's approach differed from that of the manufacturer in that they modelled the effect of treatment on PTH levels and then related this intermediate endpoint to clinical events. In the base-case analysis, patients in both arms were stratified by PTH levels. These were defined as 'controlled' (PTH 32 pmol/litre or less), 'uncontrolled' (PTH 33 to 84 pmol/litre) or 'very uncontrolled' (PTH 85 pmol/litre or more). Patients in the 'very uncontrolled' group were stratified further according to whether or not they had undergone parathyroidectomy (with or without adverse surgical events). Clinical events included cardiovascular events, fractures and death, and the probabilities of these occurring at different PTH levels were derived from a variety of different sources, mostly large cohort studies. These estimates of probability rely on a number of assumptions and are subject to uncertainty. The reduction in utility associated with an adverse event was greater in the 3 months after the event than in subsequent cycles of the model. Utility increased for subsequent cycles, but to a level that was lower than the utility before the event. The costs associated with cinacalcet, the treatment of adverse events, parathyroidectomy, monitoring of patients and concomitant medications were included in the model. It was assumed that a proportion of patients with 'very uncontrolled' PTH levels, and no patients with 'controlled' or 'uncontrolled' PTH levels, would be taking non-calcium-based phosphate binders. A wide range of sensitivity analyses were conducted. The costs of dialysis were excluded from the base-case analysis but included in a sensitivity analysis.
4.2.4 The results of the base-case analysis found that the ICER for cinacalcet was £61,900 per additional QALY. One-way sensitivity analyses carried out by the Assessment Group indicated that the model was most sensitive to the cost of cinacalcet, the relative risk of mortality for people with 'very uncontrolled' versus those with 'controlled' PTH levels, and the inclusion of costs associated with dialysis. The inclusion of dialysis costs increased the ICER by more than £10,000 per QALY.
4.2.5 The Assessment Group also modelled two further scenarios. In the first of these the intermediate marker of PTH level was removed and a direct effect of treatment on clinical outcomes was simulated. This enabled a more direct comparison with the manufacturer's submission and, as far as possible, effectiveness data were taken from the same source (pooled data from four RCTs). This analysis resulted in an ICER of £43,000 per QALY gained, excluding dialysis costs. The second additional analysis assumed that the effect of cinacalcet is mediated by levels of both PTH and Ca x P. This produced an ICER of £38,900 per QALY gained, excluding dialysis costs.
4.2.6 In an additional analysis conducted after the submission of the assessment report, the Assessment Group examined the cost effectiveness of two strategies for discontinuing cinacalcet in people whose PTH levels were not controlled by treatment. In the first scenario it was assumed that people with 'very uncontrolled' PTH levels after 3 months of treatment with cinacalcet (titration phase) would discontinue the treatment and receive standard care only. In this scenario, the ICER was reduced to £57,400 per QALY. In the second scenario it was assumed that only those people whose PTH levels reached a target of 32 pmol/litre would continue treatment. In this scenario the ICER was £44,000 per QALY.
4.2.7 Following consultation on the preliminary guidance, the manufacturer submitted a revised analysis based on the Assessment Group's modelling approach. This analysis identified strategies for using cinacalcet that could be considered more cost effective, based on applying rules for discontinuing treatment in those people for whom the drug produces an inadequate response, and for limiting the maximum dose of the drug that may be used when adjustments are made according to PTH levels. Two subgroups were considered: people with 'very uncontrolled' baseline PTH levels and people with 'uncontrolled' PTH levels. It was proposed that the subgroup of people with 'very uncontrolled' PTH levels could be treated cost-effectively as follows. The initial regimen is adjusted during the first 3 months up to a maximum of 120 mg cinacalcet per day. Those people whose PTH levels remain 'very uncontrolled' at the end of this titration period then discontinue treatment. Those whose PTH levels are now defined as 'controlled' may continue at a dose of up to 120 mg. Those who are now in the 'uncontrolled' state may continue treatment, but only at a dose of up to 60 mg. The second subgroup, that is people who start with 'uncontrolled' levels of PTH, are given cinacalcet at a dose of 30 mg daily. If at the end of 3 months their PTH levels have become 'controlled' at a dose of 30 mg, they may continue treatment. Otherwise treatment is discontinued.
4.3.1 The Committee reviewed the data available on the clinical and cost effectiveness of cinacalcet, having considered evidence on the nature of the condition and the value placed on the benefits of cinacalcet by people with hyperparathyroidism secondary to ESRD, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2 The Committee noted that the clinical trials of cinacalcet showed that it was effective in reducing levels of PTH and other biochemical markers, including serum calcium and phosphorus. It acknowledged that a reduction in adverse clinical outcomes associated with raised PTH levels, such as bone fracture and cardiovascular hospitalisation, had been observed in a post-hoc analysis of pooled safety data from several trials. However, it noted that these trials were not designed to demonstrate the clinical benefits of treatment in terms of a reduction in adverse events, and also noted that there was a lack of data relating to long-term treatment with cinacalcet. The Committee was aware of observational evidence to suggest that there is a relationship between levels of PTH, calcium and phosphate, and adverse clinical outcomes. However, it noted that there is considerable uncertainty about the extent to which intervening to correct derangements in the levels of PTH, calcium and phosphate (in particular by lowering PTH levels) is effective in reducing the risk of the adverse outcomes. The Committee also noted that many other factors relating to ESRD and its underlying causes contribute to the increased risk of serious adverse events for people on dialysis, and that these add to the uncertainty in predicting clinical benefits from changes in surrogate markers.
4.3.3 In addition to the possible risk of major adverse events associated with raised PTH levels, the Committee heard from the clinical specialists and patient experts that the biochemical disturbances associated with secondary hyperparathyroidism produce symptoms, such as pruritus, pain and muscle weakness, that reduce quality of life and may interfere with sleep and daily activities. However, the Committee heard that although cinacalcet could help to reduce the severity of these symptoms, it did not replace the need for dietary restrictions and the use of other medications such as phosphate binders and vitamin D sterols.
4.3.4 Although acknowledging the uncertainties involved with using surrogate markers, the Committee accepted the approach taken by the Assessment Group in using PTH levels as a marker of risk of adverse events in its cost-effectiveness analysis. The Committee also agreed that the additional complexity of the model, incorporating additional states to reflect different degrees of control of PTH levels, provided the best available characterisation of the course of the disease. Furthermore, this approach allowed the incorporation of health-related utilities to reflect a reduction in quality of life resulting from symptoms of 'very uncontrolled' hyperparathyroidism. The Committee accepted the validity of the Assessment Group's approach to incorporating the reduction in health-related quality of life associated with an adverse event, followed by some degree of recovery. On the basis of the cost-effectiveness analyses submitted, the Committee concluded that cinacalcet was unlikely to be a cost-effective use of NHS resources in the treatment of secondary hyperparathyroidism in patients with ESRD.
4.3.5 The Committee discussed whether cinacalcet could be used more cost-effectively by applying 'stopping rules' if the response to treatment was inadequate. In particular, the Committee considered carefully whether the strategies proposed by the manufacturer for the more cost-effective use of cinacalcet were practicable. The Committee noted that these suggested treatment strategies were based on the wide ranges of PTH levels that were specified in the model. Although accepting the Assessment Group's approach to modelling the decision problem, the Committee recognised that the ranges of PTH levels that defined health states in the model were arbitrary and were not intended to define the goals of a treatment strategy. The Committee therefore considered that the use of these ranges by the manufacturer in defining treatment strategies did not reflect clinically appropriate treatment goals and was not consistent with the dose-titration regimen described in the SPC. For example, the Committee noted that the strategies required doses of cinacalcet not to be increased above 120 mg per day, despite the 'Posology and methods of administration' section of the SPC indicating that the dose should be increased to a maximum of 180 mg per day to achieve individual treatment goals, specifically a reduction of intact PTH levels to between 150 and 300 pg/ml (15.9–31.8 pmol/litre). In addition, the proposed strategies required the cinacalcet dose to be reduced in patients who had achieved a partial response to a dose of 120 mg and yet remained in the 'uncontrolled' state. The Committee was therefore not persuaded that these treatment strategies were clinically practicable, and did not consider them an acceptable approach to maximising the clinical and cost effectiveness of treatment with cinacalcet.
4.3.6 The Committee heard from the clinical specialists that there may be a small subgroup of people with refractory hyperparathyroidism for whom cinacalcet may be an alternative to surgical parathyroidectomy. The Committee noted that there was no RCT evidence on the effectiveness of cinacalcet in people with refractory hyperparathyroidism, but considered that clinical experience existed for this subgroup of patients. The Committee noted that surgical parathyroidectomy was a treatment option for some patients with refractory disease, but there was no evidence on the clinical effectiveness or cost effectiveness of cinacalcet compared with surgical parathyroidectomy. The Committee concluded that cinacalcet should not be recommended as an alternative to parathyroidectomy.
4.3.7 The Committee was persuaded by the patient experts and clinical specialists that patients with refractory hyperparathyroidism with very high PTH levels may experience a very poor quality of life compared with those with better-controlled levels of PTH. In addition, they understood that the mortality and overall prognosis in this patient group are also significantly worse, particularly for patients with calciphylaxis. Furthermore, the Committee heard from healthcare professionals and patients that there are some people with refractory hyperparathyroidism in whom the risks of surgical parathyroidectomy are considered to be so high as to rule it out as an acceptable treatment option. The clinical specialists reported some success with cinacalcet in this subgroup of patients.
4.3.8 The Committee considered that if the high risk of adverse consequences and the poor quality of life experienced by the subgroup of patients described in 4.3.7 (in whom surgical parathyroidectomy is not possible) were taken into account, it was likely that the ICER for cinacalcet would be reduced to the extent that it could be considered a cost-effective use of NHS resources. The Committee concluded that the benefits of cinacalcet were likely to be sufficient to recommend its use in these extreme situations. However, the Committee considered that if cinacalcet does not produce an adequate response in these situations, treatment should be stopped. For these purposes the Committee proposed that an adequate response to cinacalcet treatment should be defined as a 30% or greater reduction in the plasma concentration of intact PTH after 4 months of treatment, including dose escalation as appropriate. This definition of an adequate response is based on the clinical endpoints reported in the RCTs of cinacalcet.