The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of cinacalcet hydrochloride for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had a second meeting to consider the evidence submitted, the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations, and comments from the formal consultees. The Committee has developed preliminary recommendations on the use of cinacalcet hydrochloride.

This document has been prepared for a second consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk).

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘ Guide to the technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).

• The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:
Closing date for comments: 7 September 2006
Third Appraisal Committee meeting: 19 September 2006

Details of membership of the Appraisal Committee are given in appendix A and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

Appraisal Committee's preliminary recommendations

Cinacalcet hydrochloride is not recommended for the routine treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy.

Cinacalcet hydrochloride is recommended only in those patients with refractory secondary hyperparathyroidism (including those with calciphylaxis):

• who have ‘very uncontrolled’ plasma levels of intact parathyroid hormone (defined as greater than 85 pmol/litre [800 pg/ml]) that are refractory to standard therapy and
• in whom surgical parathyroidectomy is contraindicated.

Response to treatment should be monitored regularly and treatment should be continued only if a reduction in the plasma level of intact parathyroid hormone of 30% or more is seen after 3 months’ treatment.

Clinical need and practice

The parathyroid glands produce parathyroid hormone (PTH), which controls the levels of calcium in the blood. Excessive production of this hormone is called hyperparathyroidism. When this is caused by another condition, it is called secondary hyperparathyroidism. Secondary hyperparathyroidism is a common complication of impaired renal function. Almost all people with end-stage renal disease (ESRD) have secondary hyperparathyroidism. Two UK studies have estimated the annual incidence of ESRD to be 132 and 148 per million population. A high proportion of people with ESRD receive dialysis; it is estimated that approximately 100 people per million population begin dialysis each year.

The development of secondary hyperparathyroidism in people with impaired renal function is complicated. It occurs as a result of failure of the excretory function of the kidney (impaired excretion of phosphate and impaired reabsorption of calcium) and of the endocrine function of the kidney (reduced hydroxylation of inactive forms of vitamin D to the active form, calcitriol). In the early stages of renal impairment, phosphate excretion is reduced. Initially, this does not lead to high levels of phosphate in the blood (hyperphosphataemia) because increased secretion of PTH stimulates the kidneys to excrete more phosphate. When renal impairment progresses to the moderate stage, the kidneys can no longer eliminate more phosphate in response to increased PTH secretion and phosphate levels begin to rise. Hyperphosphataemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol. Low levels of calcitriol lead to reduced intestinal absorption of calcium, leading in turn to hypocalcaemia. Hypocalcaemia, low calcitriol levels and hyperphosphataemia all independently stimulate PTH synthesis and secretion. As these chronic stimuli persist, the parathyroid glands become enlarged and begin to function autonomously, continuing to secrete PTH even if hypocalcaemia is corrected. This condition is referred to as ‘refractory’ hyperparathyroidism and is also sometimes called ‘tertiary’ hyperparathyroidism. PTH levels become extremely elevated and this causes calcium and phosphate to be released from bone. Hyperphosphataemia is exacerbated and hypercalcaemia may occur.

Secondary hyperparathyroidism is associated with clinical complications involving the bones and other tissues. Bone disease (renal osteodystrophy) is present in about 70% of people starting dialysis. It is a multifactorial disease but secondary hyperparathyroidism is an important contributor to its development. Renal osteodystrophy manifests as bone pain, bone deformity and pathological fracture and is a major cause of disability in people with ESRD. A study conducted in the USA including 40,538 people on haemodialysis found that serum phosphorous concentration was statistically significantly related to hospitalisation for fracture. Time on dialysis was also strongly associated with hospitalisation for fracture.

People with kidney disease have a much higher risk of cardiovascular disease and associated mortality compared with the general population. This is a result of multiple factors, but derangements in calcium and phosphate homoeostasis appear to contribute. Hyperphosphataemia and elevated calcium phosphorus product (the multiple of the serum levels of calcium and phosphorus) are associated with cardiovascular calcification, including the aorta, carotid and coronary arteries, the cardiac valves and myocardial muscle.

Calcification can also be seen in other soft tissues including the lung, the conjunctiva, periarticular tissues and the breast. Calciphylaxis (calcific uraemic arteriolopathy) is a rare but serious complication that can occur in people with ESRD. It appears as painful, red cutaneous nodules (singular or numerous) that can often progress rapidly to ulceration, necrosis and sepsis. On biopsy, arteriolar calcification of the subcutaneous fat and dermis is seen. Mortality is high; rates of between 45% and 65% have been reported in people with this complication.

The aim of treatment in secondary hyperparathyroidism is to manage levels of phosphate, PTH and calcium. Conventional therapy includes dietary modification to reduce phosphate intake, the use of phosphate binders, hydroxylated vitamin D sterols (calcitriol, alfacalcidol) or the synthetic vitamin D analogue paricalcitol, and modification of the dialysis regimen. In severe hyperparathyroidism, total or partial surgical removal of the parathyroid glands may be needed.

Reducing phosphate in the diet while maintaining adequate nutritional intake is difficult, because many sources of protein are also high in phosphate. Phosphate binders can be taken with meals to reduce phosphate absorption from the gut. In the past aluminium hydroxide was commonly used as a phosphate binder, but concern about aluminium toxicity in people receiving dialysis means that it is no longer widely used for this purpose. Calcium acetate and calcium carbonate are the most commonly used phosphate binders, but calcium salts are contraindicated in hypercalcaemia. Sevelamer is a non-calcium-containing phosphate-binding agent.

Vitamin D compounds that do not need renal hydroxylation for activation have been used in the treatment of secondary hyperparathyroidism in ESRD. However, doses that are capable of suppressing PTH secretion may lead to hypercalcaemia and a decline in renal function. By increasing intestinal absorption of calcium and phosphate, the risk of vascular calcification may be increased.

Phosphate clearance can be improved by intensifying the dialysis regimen. The most usual haemodialysis prescription is for 4 hours three times per week. Slow prolonged dialysis (over the course of 8 hours or more at night) or more frequent (daily) dialysis improves phosphate loss. Limitations on the availability of dialysis facilities mean that this option may be feasible only for some patients on home dialysis.

Surgical parathyroidectomy can be subtotal, total, or total with some parathyroid tissue reimplanted in a site such as the arm. Perioperative risk is greater in people with renal failure than in people with normal renal function, and there is the additional risk that any remaining parathyroid tissue will become hyperplastic and require repeat surgery.

The technology

Cinacalcet hydrochloride (Amgen) is a calcimimetic agent; that is, it increases the sensitivity of the calcium-sensing receptor to extracellular calcium ions, thereby inhibiting the release of PTH. It is licensed for treatment of secondary hyperparathyroidism in patients with ESRD on maintenance dialysis therapy. It may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate. It is initiated at a dose of 30 mg once daily, titrated every 2–4 weeks to a maximum of 180 mg once daily to reach a target intact PTH level of between 15.9 and 31.8 pmol/litre.

Because cinacalcet hydrochloride lowers calcium levels, it is contraindicated if serum calcium is below the lower limit of the normal range. The most commonly reported adverse effects in clinical trials were nausea and vomiting. These were mild to moderate in nature and transient in most cases. For full details of side effects and contraindications, see the summary of product characteristics.

The drug costs of treatment with cinacalcet hydrochloride are between £1646 and £9110 per year depending on the dose administered (excluding VAT; ‘British national formulary’ edition 51). Costs may vary in different settings because of negotiated procurement discounts.

Evidence and interpretation

The Appraisal Committee considered evidence from a number of sources (see appendix B).

Clinical effectiveness

The systematic review carried out by the Assessment Group (see appendix B) identified seven published reports of randomised controlled trials (RCTs) of cinacalcet hydrochloride 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 hydrochloride, 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 hydrochloride. All studies were designed to assess biochemical endpoints (namely changes in serum PTH, calcium, phosphate and calcium phosphorus product [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.

Improvements in mean levels of PTH, calcium, phosphate and Ca x P observed in the trials were statistically significantly greater in the cinacalcet hydrochloride groups in most of the studies that reported these endpoints. Generally, patients receiving cinacalcet hydrochloride 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 change in serum phosphate levels (n= 71 and n = 48), differences in change between the groups were not statistically significant, and in the smaller of these two studies patients receiving placebo had a greater reduction in phosphate compared with those receiving cinacalcet hydrochloride. However, these two studies were not designed or powered to detect clinically meaningful differences in serum phosphate.

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 hydrochloride, versus 5% of patients receiving placebo (p < 0.001). In these studies target intact PTH was defined as a level of less 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 were 53% versus 6% (n = 48, statistical significance not reported) and 44% versus 20% (n = 71, p = 0.029).

Statistically significantly more patients who were treated with cinacalcet hydrochloride 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 hydrochloride 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 hydrochloride 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).

A post-hoc analysis of pooled data from four RCTs designed to investigate changes in biochemical markers (n = 1184) assessed the effect of cinacalcet hydrochloride on the clinical outcomes of fracture, cardiovascular hospitalisation, all-cause hospitalisation, parathyroidectomy and mortality compared with placebo. No statistically significant difference was 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.

The same analysis also reported combined data on health-related quality of life, based on the SF-36 instrument. 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 mean. For the physical component summary score there was a 0.5-unit improvement in the cinacalcet hydrochloride arms compared with a 0.8-unit decrease in the control arms (p = 0.01); for bodily pain scale there was a 0.6-unit improvement in the cinacalcet hydrochloride 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 hydrochloride 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 reduction in bone pain was an important benefit of treatment.

The Assessment Group reported subgroup analyses by baseline intact PTH, serum Ca x P, serum calcium, serum phosphate 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 hydrochloride may be more effective in less advanced disease, but were cautious about interpreting these findings.

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 hydrochloride. The primary endpoint was the proportion of patients with a mean 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 hydrochloride arm versus 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 hydrochloride arm), the mean relative dose of vitamin D sterol decreased by 22% in the cinacalcet hydrochloride 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 hydrochloride.

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 hydrochloride and the Assessment Group developed its own economic model. Both models were cost–utility analyses comparing cinacalcet hydrochloride 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.

The model submitted by Amgen 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 hydrochloride on the relative risks for these outcomes was based on 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 hydrochloride.

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 further stratified 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. For subsequent cycles of the model utility increased, 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 and 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.

The results of the base-case analysis found that the ICER 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 hydrochloride, the relative risk of mortality for people with very uncontrolled PTH versus those with controlled PTH and the inclusion of costs associated with dialysis. The inclusion of dialysis costs increased the ICER by more than £10,000 per QALY.

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 excluding dialysis costs. The second additional analysis assumes that the effect of cinacalcet hydrochloride is mediated by levels of both PTH and Ca x P. This produced an ICER of £38,900 per QALY gained, excluding dialysis costs.

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 hydrochloride 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 hydrochloride (titration phase) would discontinue cinacalcet hydrochloride and receive standard care only. In this scenario, the ICER reduced to £57,400 per QALY. In the second scenario it was assumed that only those who reached target PTH levels of 32 pmol/litre would continue treatment. In this scenario the ICER was £44,000 per QALY.

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 hydrochloride that could be considered more cost effective, based on applying rules for discontinuing treatment in those 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. According to this analysis, it was proposed that the subgroup of people with very uncontrolled PTH 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 hydrochloride per day. Those people who remain very uncontrolled at the end of this titration period then discontinue treatment. Those whose PTH levels are then defined as controlled may continue at a dose of up to 120 mg. Those who move to the uncontrolled state may continue treatment, but only at a dose of up to 60 mg. Those who start with uncontrolled levels of PTH are given cinacalcet hydrochloride 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.

The Committee reviewed the data available on the clinical and cost effectiveness of cinacalcet hydrochloride, having considered evidence on the nature of the condition and the value placed on the benefits of cinacalcet hydrochloride by people with hyperparathyroidism secondary to ESRD, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee noted that the clinical trials of cinacalcet hydrochloride showed that it was effective in reducing levels of PTH and other biochemical markers including serum calcium and phosphate. 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 reduction in adverse effects and also noted that there was a lack of data relating to long-term treatment with cinacalcet hydrochloride. The Committee was aware of observational evidence to suggest that there was a relationship between levels of PTH, calcium and phosphate, and adverse clinical outcomes. However it noted that there was 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) was effective in reducing the risk of the adverse outcomes. The Committee also noted that people on dialysis have many other factors that contribute to their increased risk of serious adverse events, and that these add to the uncertainty in predicting clinical benefits from changes in surrogate markers.

In addition to the possible risk of major adverse events associated with raised PTH levels, the Committee heard from the clinical and patient experts at the meeting that the biochemical disturbances associated with secondary hyperparathyroidism produced symptoms, such as pruritus, pain and muscle weakness, that were detrimental to quality of life and could interfere with sleep and daily activities. However, the Committee heard that although cinacalcet hydrochloride could help 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.

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, 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 hydrochloride was unlikely to be a cost-effective use of NHS resources in the treatment of secondary hyperparathyroidism.

The Committee discussed whether cinacalcet hydrochloride could be used cost-effectively if ‘stopping rules’ for non/inadequate responders were applied. In particular, the Committee carefully considered whether the strategies proposed by the manufacturer for cost-effective use of cinacalcet hydrochloride were practicable. It considered that these treatment strategies were based on the thresholds set by the model and did not reflect clinically appropriate treatment goals consistent with the product’s UK marketing authorisation. In addition the Committee considered that these biochemical thresholds did not necessarily reflect the clinical-effectiveness end points of relevance to patients (for example, the reduction of adverse events). The Committee was not persuaded that these treatment strategies were an acceptable approach to maximising the cost effectiveness of treatment with cinacalcet hydrochloride.

The Committee heard from the experts that there may be a small subgroup of people with refractory or ‘tertiary’ hyperparathyroidism for whom cinacalcet hydrochloride may be an alternative to surgical parathyroidectomy. This option may be particularly useful if surgical risk is considered to be high. The Committee noted that there was insufficient clinical evidence on the effectiveness of cinacalcet hydrochloride in this subgroup, and there was no evidence on the clinical effectiveness of cinacalcet hydrochloride compared with surgical parathyroidectomy. Although cost-effectiveness analysis suggested that cinacalcet hydrochloride was less cost effective in people with very uncontrolled hyperparathyroidism, the extent to which this analysis reflected the population with refractory disease was not clear. The Committee also heard from healthcare professionals and patients that there were some people with refractory disease, including people with calciphylaxis, for whom risks of parathyroidectomy outweigh the potential benefits. The Committee took into account the lack of available treatment options for this small group of patients and the particularly poor prognosis of those with calciphylaxis. The Committee heard from the healthcare professionals that there was limited evidence from case reports of successful treatment with cinacalcet hydrochloride in this subgroup of patients. The Committee was therefore persuaded that the benefits of cinacalcet hydrochloride 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. The Committee proposed that a 30% or more reduction in plasma intact PTH concentration after 3 months treatment would indicate an adequate response based on the clinical endpoints reported in RCTs of cinacalcet hydrochloride.

Implementation

'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website

Proposed recommendations for further research

The Committee identified a need for long-term clinical studies that are designed to evaluate the effect of cinacalcet hydrochloride on clinical outcomes (in particular, fracture and cardiovascular events). Studies to establish the multivariate relationship between biochemical disruption in secondary hyperparathyroidism and these clinical outcomes are also recommended.

The Committee also noted that more research is needed on on the effect of cinacalcet hydrochloride in people with ESRD with particular clinical needs, specifically people with tertiary or refractory secondary hyperparathyroidism, people awaiting kidney transplants from living donors, people with calciphylaxis, people with recurrent hyperparathyroidism after parathyroidectomy, and people in whom surgical parathyroidectomy is contraindicated.

Related guidance

NICE has issued the following related technology appraisal guidance.

Renal failure: home versus hospital haemodialysis. NICE technology appraisal no. 48 (2002). Available from: www.nice.org.uk/TA048

NICE is in the process of producing the following clinical guideline.

Kidney disease: early identification and management of adults with chronic kidney disease in primary and secondary care (publication expected September 2008).

Proposed date for review of guidance

It is proposed that the guidance on this technology is considered for review in December 2009. The Institute would particularly welcome comment on this proposed date.

David Barnett

Chair, Appraisal Committee

July 2006

The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice-chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

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
Radiologist, St George's Hospital, London

Professor A E Ades
MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol

Dr Tom Aslan
General Practitioner, Stockwell, London

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Mrs Elizabeth Brain
Lay Representative

Dr Karl Claxton
Health Economist, University of York

Dr Richard Cookson
Senior Lecturer in Health Economics, School of Medicine Health Policy and Practice, University of East Anglia

Mrs Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Professor Christopher Eccleston
Director, Pain Management Unit, University of Bath

Dr Paul Ewings
Statistician, Taunton and Somerset NHS Trust, Taunton

Professor John Geddes
Professor of Epidemiological Psychiatry, University of Oxford

Mr John Goulston
Director of Finance, Barts and the London NHS Trust

Mr Adrian Griffin
Health Outcomes Manager, Johnson & Johnson Medical Ltd

Ms Linda Hands
Consultant Surgeon, John Radcliffe Hospital

Dr Elizabeth Haxby
Lead Clinician in Clinical Risk Management, Royal Brompton Hospital

Dr Rowan Hillson
Consultant Physician, Diabeticare, The Hillingdon Hospital

Dr Catherine Jackson
Clinical Lecturer in Primary Care Medicine, University of Dundee

Professor Richard Lilford
Professor of Clinical Epidemiology, Department of Public Health and Epidemiology, University of Birmingham

Dr Simon Mitchell
Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester

Ms Judith Paget
Chief Executive, Caerphilly Local Health Board, Wales

Dr Katherine Payne
Health Economist, The North West Genetics Knowledge Park, The University of Manchester

Dr Ann Richardson
Independent Research Consultant

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Mr Mike Spencer
General Manager, Clinical Support Services, Cardiff and Vale NHS Trust

Professor Andrew Stevens (Vice Chair)
Professor of Public Health, University of Birmingham

Dr Cathryn Thomas
General Practitioner, and Associate Professor, Department of Primary Care and General Practice, University of Birmingham

Simon Thomas
Consultant Physician, General Medicine and Clinical Pharmacology, Newcastle Hospitals NHS Trust

Dr Norman Vetter
Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff

Professor Mary Watkins
Professor of Nursing, University of Plymouth

Dr Paul Watson
Medical Director, Essex Strategic Health Authority

B. NICE Project Team

Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute.

Kate Burslem
Technical Lead, NICE project team

Louise Longworth
Technical Advisor, NICE project team

Janet Robertson
Technical Advisor, NICE project team

Alana Miller
Project Manager, NICE project team

Appendix B. Sources of evidence considered by the Committee

The assessment report for this appraisal was prepared by Peninsula Technology Assessment Group.

Garside R, Pitt M, Anderson R, et al, The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation, 16 March 2006.

The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and assessment report. They are also invited to comment on the appraisal consultation document and consultee organisations are provided with the opportunity to appeal against the final appraisal determination.

I.     Manufacturer/sponsors:

• Amgen (cinacalcet hydrochloride)

II    Professional/specialist and patient/carer groups:

• British Kidney Patient Association
• British Thyroid Foundation
• Kidney Alliance
• Long Term Medical Conditions Alliance
• National Kidney Federation
• Association of Renal Industries
• Association of Renal Technologists
• British Dietetic Association
• British Renal Society
• British Thyroid Association
• National Kidney Research Fund
• Renal Association
• Renal Pharmacy Group
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• Royal College of Surgeons
• Royal Pharmaceutical Society
• Society for District General Hospital Nephrologists
• Society for Endocrinology
• Department of Health
• Huntingdonshire Primary Care Trust
• North Eastern Derbyshire Primary Care Trust

III     Commentator organisations (without the right of appeal):

• NHS Confederation
• NHS Purchasing and Supplies Agency
• NHS Quality Improvement Scotland
• British National Formulary
• Welsh Assembly Government

The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on cinacalcet hydrochloride for the treatment of hyperparathyroidism secondary to impaired renal function by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the appraisal consultation document.

• Dr Neil Gittoes, Consultant Endocrinologist, nominated by the Royal College of Physicians – clinical expert
• Dr Alastair Hutchison, Consultant Renal Physician, nominated by the Royal College of Physicians – clinical expert
• Christopher Payne, nominated by the National Kidney Federation – patient expert
• Steve Rowe, nominated by the National Kidney Federation – patient expert