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Degarelix for advanced hormone dependent prostate cancer South West Peninsula checs assessment Commissioning Decision (made by the Peninsula Health Technology Commissioning Group) Clinical case: Equivocal Cost-effectiveness case: Restricted cost-effectiveness Commissioning decision: This treatment will not be routinely commissioned Date issued: March 2010 Rationale for Commissioning Decision A clinical trial has demonstrated that degarelix reduces testosterone to similar levels over one year of treatment compared to current therapy with gonadorelin analogues. This is accepted as a measure of achieving similar disease control. There are no data on which to make a judgement on longer term survival. The Group accepted that there is no initial, short-term rise in testosterone levels upon initiation of degarelix therapy, unlike the situation that occurs on initiation of gonadorelin analogues. There are currently no data demonstrating a reduction in clinical events occurring around the time of initiation of therapy compared to gonadorelin analogues. The Group considered that there was insufficient evidence of clinical benefit compared to current standard therapy with gonadorelin analogues on which to base a case for its use at a price that is greater than that of the gonadorelin analogues. NOT TO BE USED FOR COMMERCIAL OR MARKETING PURPOSES. PRODUCED TO INFORM LOCAL DECISION MAKING. 1 checs assessments checs (Clinical & Health Economic Commissioning Support) assessments are produced by the operations team of the Peninsula Health Technology Commissioning Group co-ordinated through NHS Devon. This NHS initiative was set up to provide commissioners with high quality evidence in the form of health technology assessments of clinical evidence and cost effectiveness to support local decision making. checs assessments provide Rapid access to the results of health technology assessment. Assessments are produced for medicines and indications for which there is no NICE Technology Appraisal Guidance. Assessments that are based on published information and NHS clinical expertise. The process does not include submissions from pharmaceutical companies Concise reports clearly stating the outcome of the clinical and costeffectiveness assessments and the rationale for the commissioning decision in the South West peninsula The estimated price at which medicines may be cost-effective. Enabling commissioners to explore ways in which value-based pricing can be achieved at the local or regional level for medicines which are clinically effective but not cost-effective Support for the cost effectiveness analysis has been provided by PenCLAHRC at the Peninsula College of Medicine and Dentistry (Universities of Exeter and Plymouth) through work partially funded by the National Institute of Health Research (NIHR). This collaboration gives the local NHS access to a broad range of expert resources in health technology assessment including researchers with experience of producing assessments for NICE. A review of the clinical evidence is undertaken by the clinical effectiveness team within Public Health of NHS Devon. Clinical aspects related to the treatments are discussed with clinicians involved in the care of patients. Publication of the original research undertaken for these assessments is sought in peer reviewed journals. checs assessments are made available in advance of this to assist other NHS bodies in their decision making. The authors have no competing interests to declare Peninsula Health Technology Commissioning Group The Peninsula Health Technology Commissioning Group is a collaborative commisisiong arrangement of the four PCTs in the South West peninsula (NHS Cornwall & Isles of Scilly, NHS Devon, NHS Plymouth and Torbay Care Trust). The commissioning group takes decisions on the commissioning of treatments on behalf of the constituent PCTs. These decisions are made after consideration of the clinical and cost effectiveness of the treatment, the financial impact and comments made in clinician and patient group submissions. Membership of the group is drawn from a wide array of local stakeholders including clinicians, public health, PCT commissioners, lay members and academics. The decisions of the Peninsula Health Technology Commissioning Group are available at : http://www.devonpct.nhs.uk/SWPHTCG/SWPHTCG_Commissioning_decisions2.aspx 2 Executive Summary Degarelix is a type of hormone therapy for use in advanced prostate cancer. It acts by blocking the gonadotropin releasing hormone (GnRH) receptor producing a rapid reduction in testosterone and prostate specific antigen (PSA) and avoids the initial testosterone surge (‘flare’) associated with luteinising hormone releasing hormone analogues (LHRHa). Current standard treatment is to use a luteinising hormone releasing hormone analogue (LHRHa) such as triptorelin, goserelin or leuprorelin, plus oral antiandrogens commenced a few days before the LHRHa and continued for about three weeks to block the effects of the ‘flare’. There is evidence from one open-label, randomised, controlled trial demonstrating that degarelix reduces testosterone to similar levels over one year of treatment compared to current therapy with LHRHa therapy with leuprorelin. No evidence was found that readily provided characterisation of biochemical measures and clinical events related to testosterone flare. The clinical benefit of avoidance of tumour flare with degarelix has not been assessed in clinical trials as an outcome measure. The manufacturer’s submissions to the Scottish Medicines Consortium (SMC) and All Wales Medicines Strategy Group (AWMSG) in 2009 were not accepted due to weaknesses in the health economic models. In January 2011 the SMC published an acceptance of a resubmitted case. The cost utility model supporting this was based upon secondary endpoint data of PSA recurrence derived from a one year study and interim results from an extension phase extrapolated over 20 years. In this model the increased drug cost of degarelix were offset by reduced costs of more expensive therapy incurred upon disease progression. Goserelin was the comparator used in the model, whilst leuprorelin was the comparator used in the trial. The acceptance is contingent upon the availability of a discounted price for degarelix, the detail of which was not revealed by the SMC. Triptorelin is recommended in formularies across the Peninsula and is cheaper than the goserelin used in the SMC/AWMSG model and was used as the comparator in our model. The European Medicines Agency identify that the major clinical added value of degarelix is the avoidance of testosterone flare upon initiation of treatment. The Summary of Product Characteristics for degarelix clearly states that data on clinical experience of efficacy and safety is limited to one year. We present a decision analytic model (consisting of a decision tree and a Markov submodel), to estimate the cost effectiveness of degarelix compared to triptorelin plus short term anti-androgen cover in the management of patients with metastatic prostate cancer. The model focuses on the costs associated with the serious complications (spinal cord compression and bladder outlet obstruction) of testosterone flare which occurs on initiation of LHRHa therapy. These outcomes have not been assessed in clinical trials of degarelix but the absence of biochemical flare has been demonstrated. This model assumes that the long term effects of degarelix and triptorelin on prostate cancer are 3 equivalent and therefore assesses the cost effectiveness of the short term proven biochemical advantage. In the base case scenario, the ICER for degarelix compared to triptorelin plus anti androgen was £59,000 per QALY gained. A sensitivity analysis was undertaken to examine all of the uncertainties of the data. The model suggests that the biggest sources of variation to the cost effectiveness case are the price of degarelix, the rate of progression of the disease, the proportion of patients who suffer spinal cord compression on initiation of LHRH therapy, and the proportion of cases of SCC that are severe. The ICER was very sensitive to the price of degarelix. If the price was 70% of the market price, degarelix dominated, i.e. it produces more QALYs and incurs less total costs compared with triptorelin plus anti-androgen. Clinicians identified the following subgroups in which additional benefit with degarelix over an LHRHa may be present o patients at high risk from a clinical flare o patients presenting with spinal cord compression or bladder outlet obstruction. We found no suitable evidence permitting quantification of any benefits in these specific subgroups and hence our model is restricted to the general population of men with metastatic prostate cancer This assessment demonstrates that at the UK list price, degarelix does not represent a cost effective use of NHS resources. If the price of degarelix were to be reduced by 30% it might reduce overall NHS costs associated with hormonal treatment of advanced prostate cancer, but there is much uncertainty in the clinical data. Even at this price the drug acquisition cost is greater than alternative treatment with triptorelin. These results support the SMC position that degarelix should only be used if a discount scheme is available, but the details of this scheme have not been made publically available. It is up to individual commissioning organisations to determine if any scheme offered is acceptable, giving consideration to drug acquisition cost and the administrative cost and burden of operating the scheme. 4 Abridged Heath Technology Assessment 1. The Technology Degarelix is a new treatment for advanced hormone dependent prostate cancer. It presents a novel form of hormone manipulation by blocking the gonadotropin releasing hormone (GnRH) receptor leading to a rapid reduction in testosterone and prostate specific antigen (PSA). The current standard treatment is to use an analogue of luteinising hormone releasing hormone (LHRHa) such as triptorelin, goserelin or leuprorelin. These types of treatments produce an initial, short-term stimulation of testosterone release followed by a reduction to castrate levels within 1 month. The initial stimulation, which typically occurs within the first few days of treatment and persists for about a week, is called a ‘flare’. This biochemical ‘flare’ may be accompanied with clinical symptoms. Current practice, supported by NICE guidance and BNF recommendation is to commence therapy with oral anti-androgens a few days before initiation of the LHRHa and continue for about 3 weeks to block the effects of the flare. However, there is a lack of conclusive evidence to support the clinical benefit of the routine application of this prevention strategy. Degarelix does not initially stimulate testosterone production. As there is no biochemical flare, the prescription of anti-androgens is not required. 2. The clinical need Prostate cells are dependent on androgens, such as testosterone, to stimulate growth. As most of the circulating testosterone is derived from the testes, prostate cancer growth can be slowed by surgical castration. Medical castration with LHRHa hormone therapy is a well established alternative option in the management of prostate cancer, which many men find more acceptable. The initial stimulation of testosterone release brought about by LHRHa therapy can produce troublesome symptoms such as bone pain. More serious complications are comparatively rare but can include urinary obstruction and spinal cord compression, which may lead to permanent disability. Due to its mechanism of action, degarelix does not cause this testosterone flare. This has been identified as the significant clinical advance of interest for patients with metastatic disease. Data for England suggests that 8.5% of new presentations of prostate cancer have metastatic disease (British Association of Urological Surgeons). In 2007 there were 1,249 new registrations of prostate cancer in the South West Peninsula. 3. Strategic direction There is no NICE technology appraisal of degarelix, nor is one planned. Initially the Scottish Medicines Consortium (SMC) recommended that degarelix not be used in NHS Scotland as the economic case was not sufficiently robust. This decision was 5 reversed in January 2011 after a resubmission. The All Wales Medicines Strategy Group have recommended that it is not used in Wales as the case for cost effectiveness has not been proven. NICE Clinical Guideline CG58 (Prostate Cancer) was produced before degarelix was available. Recommendations on the use of hormonal therapy are dependant on the stage of the disease: Localised prostate cancer: adjuvant hormonal therapy for a minimum of 2 years in men receiving radical radiotherapy for localised prostate cancer who have a Gleason score of ≥8 (high risk). Hormonal therapies are not routinely recommended in men who have a biochemical relapse unless they have symptomatic local progression or metastatic disease or a PSA doubling time <3 months. 4. Locally advanced prostate cancer: hormonal therapy is recommended as neoadjuvant treatment for 3-6 months prior to radical radiotherapy and for 2 years afterwards in men with a Gleason score ≥8. It is not recommended in addition to radical prostatectomy. Metastatic prostate cancer: Hormonal therapy should be offered as an alternative to bilateral orchidectomy. The treatments have been shown to have similar efficacy. Orchidectomy is more cost effective but patient preference may be an issue. Although there is no long term evidence of effectiveness intermittent androgen blockade (using combined LHRH analogue and anti-androgen) may also be offered. Evidence of Clinical Effectiveness 4.1 Identification of key clinical trials The Cochrane Clinical Trials database and PubMed were searched for relevant studies. A PubMed search was conducted using the terms ‘degarelix’, ‘prostate cancer’, ‘advanced prostate cancer’, ‘hormonal treatment’. This was supplemented with additional searches to obtain specific parameter estimates for the economic model. Table 1 lists the relevant studies of degarelix identified. Table 1: Summary of Degarelix studies Source Klotz 2008 Gittleman 2008 Van Poppel 2008 Tombal 2009 Schroder 2009 Purpose of study Phase III open label – efficacy and safety Phase II dose finding study Phase II dose finding Sub-analysis of Klotz trial Sub-analysis of Klotz trial Additional data for the health economic model has been extracted from published papers. 6 4.2 Overview of clinical evidence Non inferiority to leuprorelin in achieving castrate levels of testosterone from day 28 to day 364 has been demonstrated in a 1-year, open label, randomised controlled trial of 610 men with prostate cancer (Klotz, 2008). This trial compared leuprorelin 7.5mg monthly, twice its UK licensed dose, with two different dose regimens of degarelix; one arm was the licensed regimen, the other used twice the maintenance dose. The proportion of responders was very similar between the treatments and also across the different doses of degarelix studied. Degarelix achieved a more rapid reduction in PSA levels than leuprorelin monotherapy (64% reduction at day 14 with degarelix compared to 18% reduction with leuprorelin). However, in patients who received leuprorelin with concomitant bicalutamide, which could be prescribed as flare cover at the investigators discretion, the PSA reduction was similar to that achieved with degarelix. A testosterone surge was observed in 80% of patients on leuprorelin compared to one on degarelix in the non-licensed dose group. There was no difference in the rate of PSA failure (defined as an increase of 50% from nadir and ≥ 5ng/ml) between any of the groups. The higher rate of testosterone surge in the leuprorelin group is pharmacologically predictable but only 11% of patients were prescribed anti-androgen cover. It is not clear what the impact of the high dose of leuprorelin used is, either on efficacy or adverse event profile. Schroder (2009) reports changes in alkaline phopsphatase levels, a non-specific biochemical marker of bone turnover, which were observed to be suppressed to lower levels with degarelix than with leuprorelin. It is unclear what the clinical effects of this are: the authors suggest that degarelix might offer better control of serum alkaline phosphatase and might prolong control of skeletal metastases compared to LHRHa over a 1-year treatment period. Sub analysis reported by Tombal (2009) found lower incidence of PSA failure and death in patients given degarelix compared to leuprorelin. However, there are a number of limitations that require consideration. Firstly, these are exploratory analyses involving a small number of events. Secondly, the risk of disease progression is associated with baseline parameters which were not stratified at baseline. PSA recurrence was experienced by the same proportion of patients in the leuprorelin and high-dose degarelix groups which both had more patients with metastatic disease compared to the licensed-dose degarelix group. More patients in the leuprorelin and high dose degarelix groups had metastatic disease at baseline and PSA recurrence was experienced by the same proportion of patients in each group. Furthermore, the median age of patients in the leuprorelin group was 2 years older than the degarelix groups. The median age in the two degarelix groups was the same as was the number of deaths. It is thus not clear if the probability of death is related to a treatment effect or the age of the patients. Fewer patients in the licensed-dose degarelix group were also in the highest group of baseline PSA (>50ng/ml). There was no difference in risk of PSA recurrence or death in analyses that adjusted for baseline disease stage or PSA level. 4.3 Conclusions on clinical evidence Data are limited to one year of follow up of surrogate biochemical markers. The biochemical response in terms of testosterone suppression has been shown to be 7 non inferior to leuprorelin. Survival has not been adequately assessed as a planned outcome measure in a clinical trial. Clinical opinion is that the principal benefit of degarelix would be the absence of testosterone flare. Secondary endpoint data support that degarelix is not associated with this effect. The clinical benefit of this is dependant on the circumstances in which degarelix would be used. Avoidance of spinal cord compression complications and bladder outlet obstruction are those of most clinical interest. We could find no trial work that examined comparative rates of these events. A high rate of biochemical testosterone flare was observed in the leuprorelin group in which only a minority of patients were given prophylactic androgen cover for any adverse events this might be associated with. This is in contrast to routine clinical practice when initiating LHRHa in patients with metastatic disease. Despite this, no serious adverse events associated with testosterone flare were reported in the trial. 5. Discussion of evidence on safety In the major comparative study of degarelix and leuprorelin there were a similar proportion of treatment emergent adverse events in the 3 groups. The most common were pharmacological predictable effects such as hot flushes (26%) and weight gain (7%). Drug related adverse events were more common in the degarelix groups, principally due to a higher incidence of injection site reactions (40% vs 1 patient with leuprorelin). Excluding injection site reactions, the incidence of adverse events was similar for degarelix and leuprorelin. There were no reported instances of the serious consequences of testosterone flare that are the subject of this assessment in any of the treatment arms. The SPC lists hot flushes and injection site reactions as very common adverse events, with anaemia, weight increase, insomnia, dizziness, headache, diarrhoea, nausea, hyperhidrosis, musculoskeletal pain, gynaecomastia and fatigue as common adverse events. Many of these are expected due to testosterone suppression. 6. Summary of the clinical case The clinical case is considered to be: equivocal. Appendix 1 shows the criteria used to define the clinical case. In summary, data are available assessing surrogate outcomes only. The attainment of castrate levels of testosterone is accepted as a useful surrogate to assess efficacy in achieving control of hormone dependent disease. Degarelix achieves this a few weeks sooner than occurs with LHRHa and maintains similar levels over at least 1 year. No evidence was found that readily provided characterisation of biochemical measures and clinical events related to testosterone flare. The clinical benefit of avoidance of tumour flare with degarelix has not been assessed in clinical trials as an outcome measure. 7. Cost Effectiveness In 2009 the manufacturer made submissions to the SMC (2009) and the All Wales Medicines Strategy Group (2009). In both cases these included a cost-utility model for the use of degarelix in place of goserelin plus anti-androgen flare cover in 8 patients with metastatic disease. The manufacturer’s model used a three state Markov model to follow patients over a lifetime horizon (calculated at 80 months) to reflect expected average survival. The SMC noted a number of weaknesses in the economic analysis including the use of a post hoc sub group analysis indicating a non-significant difference in PSA failure rate, which could be accounted for by an imbalance at baseline, and a different clinical reaction to PSA failure from current practice. A resubmitted model was subsequently accepted by the SMC (2011). This used secondary endpoint data of PSA recurrence taken from the results of the one-year randomised trial and interim results from an extension phase. These data were extrapolated over a 20 year horizon by fitting a Weibull curve. In this model, those treated with degarelix progressed to more expensive treatments due to PSA failure at a slower rate than those treated with goserelin. This resulted in the increased acquisition costs associated with degarelix being offset by reduced subsequent treatment costs. Patients treated with degarelix were estimated to gain an extra 0.46 QALYs. The clinical data used in this model is derived from a post hoc sub group analysis which found a difference between degarelix and leuprorelin of borderline significance with wide confidence intervals and based upon low numbers. There is thus considerable uncertainty about the difference in clinical progression between degarelix and leuprorelin treated patients. The model assumes that goserelin has an equivalent effect to the leuprorelin used in the clinical trial of degarelix. Whilst the assumption of an equivalent effect of the different LHRHa may not be unreasonable, cheaper LHRHa therapy with triptorelin is available on the NHS which could have been used in the model. In the South West Peninsula, triptorelin has been adopted for several years as an alternative LHRHa to goserelin and is over £200 per year cheaper than goserelin. Additionally, the key clinical advantage noted by the EMEA (2008) and echoed by clinical opinion is the avoidance of initial testosterone surge which has been proven in the clinical study, whilst there are no conclusive data on clinical progression. Our economic evaluation, (Lu et al., 2011) considers whether using degarelix to achieve castrate levels of testosterone whilst avoiding the testosterone flare is cost effective compared to using triptorelin with anti-androgen cover. Our evaluation consists of a decision tree and a Markov submodel to estimate the cost effectiveness of degarelix compared to triptorelin plus short term anti-androgen cover in the management of patients with metastatic prostate cancer. The model takes an NHS perspective and incorporates health state utilities and costs associated with time spent receiving treatment for clinical symptoms due to initial flare, time spent receiving hormonal treatments, response, progressive disease and death. Costs and benefits were discounted at 3.5%. It was the opinion of local clinicians that the main difference in effectiveness between degarelix and triptorelin was the initial flare caused by triptorelin that may lead to two major complications, spinal cord compression (SCC) and bladder outlet obstruction (BOO). These events are poor clinical outcomes for patients and result in additional NHS expenditure. To capture the differences in costs and utilities due to these significant events within the first month of the two hormonal treatments, the model consisted of a decision tree for these short-term events. The effectiveness of the two treatments after the initial month is assumed to be the same, i.e. progression-free survival and long term survival for both treatments are assumed to be the same. A Markov submodel was used to follow patients from the end of the first month to death. The 9 time horizon of the model is 10 years after which time 96% of the patients are expected to have died. Sensitivity analyses were conducted to assess the effect of uncertainty around the model structure and the impact of variation in certain key parameters that were expected to have a strong influence of the cost effectiveness analysis. Such analyses included a variation in price of degarelix and the proportion of SCC and BOO events due to initial flare when patients are treated with triptorelin. The price of degarelix used was £305.50 for the first 240mg dose, reflective of list price plus VAT payable on hospital initiated treatment and £129.37 for the 80mg maintenance injection, the list price excluding VAT as it is assumed that treatment would continue in the community. The manufacturer offers individual PCTs a rebate scheme but the details are commercial in confidence. A sensitivity analysis was undertaken to examine the effect of the uncertainty in the data. Our analysis will help commissioning groups decide upon the acceptability of any rebate scheme they are offered. Results In the base case scenario, the ICER for degarelix compared to triptorelin plus anti androgen was £59,000 per QALY gained. 8. The model suggests that the biggest sources of variation to the cost effectiveness case are the price of degarelix, the rate of progression of the disease, the proportion of patients who suffer spinal cord compression on initiation of LHRH therapy, and the proportion of cases of SCC that are severe. Of these sources of variation the most robustly characterised parameter is the price of degarelix. The ICER was very sensitive to the price of degarelix. If the price was 70% of the market price, degarelix dominated, ie it costs less and produces more QALYs compared with triptorelin plus anti-androgen. Summary of the cost-effectiveness case The cost effectiveness case is: restricted cost effectiveness. Appendix 1 shows the criteria used to define the cost-effectiveness case. Our analysis estimates an ICER of £59,000/QALY for degarelix at list price compared to treatment with triptorelin plus short term anti androgen. There is considerable uncertainty in this finding due largely to uncertainty in the rate of serious complications of flare. Using the upper and lower bounds of the confidence intervals from the largest available data set of serious short term complications the cost/QALY varies from £28,000-£124,000. At a discount of 30% to the list price, the cost effectiveness of degarelix dominates, i.e. it achieves greater benefits at less cost than the comparator. 9. Budget Impact It was estimated that 106 patients across the South West Peninsula population of 1.6 million would be considered for treatment with degarelix. This gives an estimated additional drug acquisition cost of £79,076 expected in the first year. This 10 will be partially offset by a reduction of costs associated with spinal cord compression (1 case) and bladder outlet obstruction (up to 9 cases). If the patient cohort remains on treatment past 1-year, an additional drug acquisition cost of £76,744 is incurred with no expected offset costs from reduced clinical events. The above costs may be reduced if a PCT chooses to access a rebate scheme offered by the manufacturer. The net budget impact may then be cost saving. 10. Authors This HTA has been produced by the Peninsula Health Technology Operations Group. Clinical aspects of treatment of metastatic prostate cancer have been discussed with local specialists. Support for the cost effectiveness analysis has been provided by PenCLAHRC at the Peninsula College of Medicine and Dentistry through work partially funded by the National Institute of Health Research (NIHR). This collaboration gives access to an expert resource with experience of producing appraisals for NICE. The authors have no interests to declare. 11. Update September 2011 The full details of the cost effectiveness evaluation have been published. Lu L., Peters J., Roome C., Stein K. (2011) Cost effectiveness analysis of degarelix for advanced hormone-dependent prostate cancer. BJU Int Article first published online: 23 AUG 2011 DOI: 10.1111/j.1464-410X.2011.10434.x The Peninsula Health Technology Commissioning Group considered the implications of the SMC decision to accept the revised health economic model supporting the use of degarelix in Scotland. It was considered that the revised economic analysis would not alter the decision of the Peninsula Health Technology Commissioning Group. This was because of uncertainty in the robustness of data on disease progression, the use of goserelin as the comparator in the model, and that the principal potential advantage of degarelix as identified by the EMEA and echoed by clinical opinion was the avoidance of testosterone surge, which was not included in the model. 11 12. References All Wales Medicines Strategy Group (2009) Degarelix (Firmagon) for the treatment of advanced hormone-dependent prostate cancer. Advice No. 2109. EMEA (2008) Assessment report for Firmagon. European Medicines Agency Doc Ref EMEA/CHMP?635761/2008 Gittlema M et al. (2008) A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J Urol,180: 1986-92 Klotz L et al. (2008)The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 102: 1531-8 NICE. (2008) Prostate Cancer CG 58: diagnosis and treatment. February 2008 Summary of Product Characteristics. September 2009. Degarelix. Ferring Pharmaceuticals Ltd. Scottish Medicines Consortium (2009) Degarelix 120mg and 80mg powder and solvent for solution for injection (Firmagon). Drug Advice No 560/09. Scottish Medicines Consortium (2011) Degarelix 120mg and 80mg powder and solvent for solution for injection (Firmagon). Drug Advice No 560/09 resubmission. Tornoe C et al. (2007) Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues. Br J Clin Pharmacol 2007;63: 648-64 Van Poppel H et al.(2008) Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer. Eur Urol 54, 805-13 12 Appendix One: Peninsula Health Technology Commissioning Group Criteria used to define the clinical and cost-effectiveness case 1. Clinical case Category Generally Supportable Supportable with restrictions Equivocal Not supportable 2. Criteria There is robust, preferably reproduced, evidence of a benefit likely to be considered meaningful by patients and which is likely to be applicable to the majority of the patients. The clinical case would support commissioning. There is evidence of a benefit likely to be considered meaningful by patients with the condition to be treated but it is likely to be limited only to certain subgroups (which the Task Specific Group should define). Commissioning for use in the defined subgroup would be appropriate. There are data suggestive of a benefit but this is derived from studies which are not conclusive or where data are conflicting. Examples may also include The benefit may only be apparent in certain subgroups of patients which are not readily defined. Professional bodies may recommend treatment but this is based upon consensus rather than trial evidence of the direct benefit of the technology in the condition under consideration Data are available demonstrating evidence only of improvements in surrogate outcomes which may not translate into objective benefits likely to be considered meaningful by patients. There are significant difficulties and limitations to the data. Examples may include: Significantly different patient populations studied to that treated locally, significant doubts about the robustness of trial data. Cost effectiveness case Category Generally cost effective Restricted cost effectiveness Not cost effective Criteria Cost effectiveness considerations suggest that under general use the technology compares favourably with other interventions that have been assessed nationally as a cost effective use of NHS resources. Cost effectiveness considerations suggest that the technology only compares favourably with other nationally assessed cost effective technologies under restricted circumstances. The task specific group should describe these circumstances. Such circumstances may include identifiable sub groups, or assumptions about outcomes that have not been proven. Cost effectiveness considerations suggest that the technology is likely to have similar cost effectiveness to interventions that have been assessed nationally as not cost effective. 13