Appraisal Consultation Document: Human growth hormone (somatropin) in adults with growth hormone deficiency
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE
Appraisal Consultation Document
Human growth hormone (somatropin) in adults with growth hormone deficiency
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The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of human growth hormone (somatropin) in adults with growth hormone deficiency and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of human growth hormone (somatropin) in adults with growth hormone deficiency. This document has been prepared for 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 lthe NICE website). 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 on the Institute's website).
The key dates for this appraisal are: Closing date for comments: Thursday 20th March 2003 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. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 |
Recombinant human growth hormone (somatropin) treatment is recommended for the treatment of adults with growth hormone (GH) deficiency only if they fulfil all three of the following criteria.
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| 1.2 | The QoL status of people who are given GH treatment should be re-assessed 9 months after the initiation of therapy (an initial 3-month period of GH dose titration followed by a 6-month therapeutic trial period). GH treatment should be discontinued for those people who demonstrate a QoL improvement of less than 7 points in QoL-AGHDA score. |
| 1.3 | Patients currently receiving GH treatment at the date of publication of this guidance should be re-assessed, as part of routine follow up, by their consultant endocrinologist, and consideration given to the appropriateness of continuation of therapy, taking into account the recommendations in Section 1.1. |
| 1.4 | Children with GH deficiency should be treated as outlined in the Institute's guidance on the use of GH in children (NICE Technology Appraisal Guidance No. 42). At completion of linear growth (that is, rate < 2 cm/year), GH treatment should be stopped for 2-3 months, and then GH status should be re-assessed. GH treatment at adult doses should be re-started only in those satisfying the biochemical criteria for severe GH deficiency (as defined in Section 1.1), and continued until adult peak bone mass has been achieved (normally around 25 years of age). Following this, the decision to continue GH treatment should be based on the same criteria set out in Section 1.1. |
| 1.5 | Initiation of GH treatment, dose titration and assessment of response during the trial period should be undertaken by a consultant endocrinologist with special interest in the management of GH disorders. Thereafter, if maintenance treatment is to be prescribed in the primary care setting, it is recommended that this should be under an agreed shared-care protocol. |
| 2 | Clinical need and practice |
| 2.1 | Growth hormone, also known as somatropin, is a hormone produced by the anterior pituitary gland. It has a role in the regulation of protein, lipid and carbohydrate metabolism, as well as in increasing growth in children. Its secretion is intermittent and occurs predominantly during deep sleep. Secretion reaches maximal levels during adolescence, and then declines with age by approximately 14% per decade. |
| 2.2 | Adult GH deficiency may be of adult onset or childhood onset, and may occur as isolated GH deficiency or as part of multiple pituitary hormone deficiency. In adult onset, GH deficiency is commonly due to pituitary tumours or their treatment, and to cranial irradiation. Childhood-onset GH deficiency is often idiopathic, and may continue into adulthood. |
| 2.3 | The Society for Endocrinology estimates that the prevalence of adult-onset GH deficiency is approximately 1 in 10,000 of the adult UK population. If adults with childhood-onset GH deficiency are also considered, the prevalence may be as high as 3 in 10,000 of the adult population. This equates to approximately 12,600 adult patients with GH deficiency in England and Wales. |
| 2.4 | GH deficiency in adults may be associated with the following adverse features to a variable degree in any individual: reduced quality of life (QoL, especially reduced energy levels), altered body composition (reduced lean mass and increased fat mass, especially in the trunk), osteopenia/osteoporosis (reduced bone mineral density), dry skin (reduced sweating), reduced muscle strength and exercise capacity, lipid abnormalities (especially elevated LDL cholesterol), insulin resistance, increased levels of fibrinogen and plasminogen activator inhibitor, reduced extracellular fluid volume, increased thickness of the intima media (of blood vessels) and impaired cardiac function. |
| 2.5 | Several diagnostic tests are available for the diagnosis of GH deficiency. The insulin tolerance test (ITT) is regarded as the 'gold standard' test for adults. A general definition of severe GH deficiency in adults is a peak concentration of less than 9 mU/litre (3 ng/ml) in response to insulin-induced hypoglycaemia. When the ITT is contraindicated other tests - such as response to GH-releasing hormone, arginine or glucagon - can be used. |
| 2.6 | The clinical management of GH deficiency in adults is centred on replacement therapy with biosynthetic human GH (somatropin). However, there has been local variation in practice within the UK. The Society for Endocrinology estimates that approximately 1750 adults with GH deficiency currently receive treatment in the UK. |
| 3 | The technology |
| 3.1 | There are four preparations of GH available on the UK market for the treatment of adults: Genotropin (Pharmacia), Humatrope (Lilly), Norditropin (Novo Nordisk) and Saizen (Serono). Each product is produced by recombinant DNA technology and has a sequence identical to that of human GH. |
| 3.2 |
GH is licensed for replacement therapy in adults with pronounced GH deficiency, as diagnosed in two different provocation tests for GH deficiency. Patients must also fulfil the following criteria.
Patients who were diagnosed as GH deficient during childhood must be retested and their GH deficiency confirmed before replacement therapy with GH is started.
Patients must have GH deficiency as a result of hypothalamic or pituitary disease and at least one other hormone deficiency diagnosed (except for prolactin deficiency), and adequate replacement therapy with these hormones must be established before replacement therapy using GH may begin. |
| 3.3 | Treatment is self-administered by a daily subcutaneous injection. The initial dose is 0.2-0.3 mg (0.6-0.9 IU) daily and typically 0.27 mg (0.8 IU) daily. Dosage adjustments are then made after monthly assessments of serum levels of insulin-like growth factor-1 (a marker of GH response) for a period of 2-3 months and in response to the presence of adverse effects until a maintenance dose is achieved. The currently used median maintenance dose is 0.4 mg (1.2 IU) daily. GH requirements may decrease with age. |
| 3.4 | Side effects may include headache, arthralgia (joint pain), myalgia (muscle pain), fluid retention (peripheral oedema), mild hypertension, carpal tunnel syndrome, visual problems, nausea and vomiting, paraesthesia, antibody formation, and reactions at the injection site. Benign intracranial hypertension is a rare complication. |
| 3.5 | GH treatment is contraindicated in people with any evidence of tumour activity, in critically ill patients (for example, after complications following open heart or abdominal surgery, multiple trauma, acute respiratory failure or similar conditions) and also in patients with known hypersensitivity to GH or to any of the excipients. GH treatment is also contraindicated during pregnancy and lactation. In patients with tumours, anti-tumour therapy must be completed before starting GH therapy. |
| 3.6 | The cost of treatment depends on the dose, which is determined by the weight/size of the patient, as well as the individual GH reserve. The cost of GH (excluding VAT; British National Formulary [BNF] September 2002) is £23.18 per mg for Genotropin, £22.87 per mg for Humatrope and Saizen, and £23.42 per mg for Norditropin. The average annual cost of GH treatment is around £3350 per patient. The cost of treatment reduces by age; this is because the GH requirement decreases as people get older. |
| 4 | Evidence and interpretation |
| The Appraisal Committee considered evidence from a number of sources (see Appendix B). | |
| The Institute commissioned two Assessment Reports: one was undertaken by the Wessex Institute for Health Research and Development and the other by the University of Sheffield School of Health and Related Research (ScHARR). The Wessex Assessment Report focused on evidence from double-blind, randomised, placebo-controlled trials to evaluate the efficacy of GH treatment in terms of QoL benefits, whereas the ScHARR Assessment Report included the additional evidence that was available from observational studies and some new data from two unpublished, randomised controlled trials (RCTs). The Wessex Assessment Report also included a cost analysis of the GH treatment, and the ScHARR Assessment Report provided a detailed critique of the economic models submitted by the manufacturers. During the course of the appraisal, some of the manufacturers submitted additional data from newly reported, unpublished trials and results from updated economic analyses. | |
| 4.1 | Clinical effectiveness |
| Quality-of-life evidence from randomised controlled trials | |
| 4.1.1 | The Assessment Reports identified 17 published RCTs evaluating the effects of GH on QoL in around 900 adult patients with GH deficiency. Twenty-three different QoL assessment scales were used within a variety of trial designs. The duration of the studies was typically 6 months. The number of participants ranged from 6 to 173. Most studies included both adult- and childhood-onset GH deficiency. |
| 4.1.2 | Ten studies evaluated health-related QoL using the Nottingham health profile (NHP), but not all reported the results. Additional, unpublished data on QoL for one of the studies were made available to ScHARR. These data were supplied in confidence and have not been included in the pooled results presented below. However, including these data had only a small impact on the results of the meta-analyses and did not affect the conclusions of the ScHARR Assessment Report. |
| 4.1.3 | The analysis of the individual dimensions of the NHP found some statistically significant changes in the GH-treated group compared with the control group. |
| 4.1.4 | In one of the four published studies (the largest) that reported the social isolation dimension, the score was significantly improved in the GH-treated group compared with the placebo group. For this dimension, pooled analysis of all four studies found a small, statistically significant difference in favour of treatment (-0.3 points, 95% confidence interval, -0.4 to -0.1). The largest of the four studies that reported the emotional reactions dimension found a small but statistically significant difference in favour of treatment, but the difference was not statistically significant in the pooled analysis. |
| 4.1.5 | Five studies reported the energy dimension. One of the smaller studies found a significant difference in favour of GH treatment, but the pooled analysis of all five did not. For the sleep and physical mobility dimensions, none of the four individual studies reporting these dimensions nor the pooled analysis found a treatment effect of GH. For the pain dimension, one study found a significant difference in favour of placebo, but there was no significant difference in the pooled analysis for four studies. |
| 4.1.6 | The NHP is not designed to produce an overall total score. However, two studies reported mean total scores. Both found improvements in favour of treatment, but these were not statistically significant in either of the individual studies or in the pooled analysis. |
| 4.1.7 | Two RCTs used the 'QoL-assessment of growth hormone deficiency in adults' (QoL-AGHDA) questionnaire - a self-completed questionnaire comprising 25 questions specifically designed to assess the consequences of GH deficiency and its treatment. A high QoL-AGHDA score indicates greater impairment of QoL. One study was conducted across three centres in Spain and included 69 patients. The other was conducted in the Netherlands and recruited 30 patients. Minimal data from these studies have been published in abstract form, but further results were made available in confidence to the ScHARR review group for evaluation. |
| 4.1.8 | Data pooled from two trials reporting the Hamilton Depression Scale found in favour of GH treatment, but results were not statistically significant. GH use was associated with an improvement of 2.4 points (95% confidence interval, -4.9 to 0.1). |
| 4.1.9 | Meta-analysis of two trials reporting psychological well-being (using the Psychological General Well-being Schedule) found in favour of the GH-treated group, but the results were not statistically significant. |
| 4.1.10 | In summary, based on the evidence from RCTs, in terms of QoL the effectiveness of GH treatment in adults with GH deficiency remains unproven. Many of the available studies were of poor quality. Also, because the patients involved had comparatively normal QoL values at baseline there was little scope for improvement. Furthermore, most of the RCTs used a dosage regimen determined by the patient's weight rather than one based on a titration technique, which is now common clinical practice. This raises difficulties with using this evidence to estimate the effectiveness of currently used GH regimens. |
| Quality-of-life evidence from observational trials | |
| 4.1.11 | A 10-year study provided the longest period of observational follow-up of replacement therapy in GH deficiency. This study included patients who had previously participated in an RCT. Of the 24 patients in the original study, ten patients who had continued to receive GH continuously for 10 years were compared with 11 who had not. For the group receiving GH, QoL - as measured by the NHP - was improved over baseline in the domains of energy level and emotional reactions. Overall score was also improved. There was no change in the untreated group. However, the two groups may not be comparable, as there are a variety of reasons why patients may or may not continue treatment. Two shorter observational studies (12 months) reported improvements in overall NHP scores after GH treatment. |
| 4.1.12 | Eight observational studies of GH therapy in GH deficiency reported QoL-AGHDA scores. Three of these reported results from the largest observational data set of GH-deficient patients, the KIMS database. KIMS is the Pharmacia & Upjohn international metabolic database and pharmaco-epidemiological survey of adult GH-deficient patients receiving GH therapy. The three KIMS studies account for most of the published observational data on QoL. They each included between 300 and 665 participants. However, it is likely that data from many of the same patients were reported in all three publications. The extent to which this may have occurred is not clear. The number of participants lost to follow-up was also unclear. In these studies, the reported mean reduction in QoL-AGHDA score after GH treatment ranged from 2.8 to 4.8. The remaining five studies that used the QoL-AGHDA included between 10 and 65 patients, and reported reductions in mean QoL-AGHDA scores ranging from 3 to 7.2. |
| 4.1.13 | A formal meta-analysis of the observational data was not performed. However, a crude estimate of average change in QoL-AGHDA was made. This suggested that, across the studies (weighted by number of patients), the average change from baseline in QoL-AGHDA after GH treatment was 3.7 points. |
| 4.1.14 | In clinical studies, improvements in QoL were observed within 3-6 months of initiating treatment. Limited data from observational studies suggested that the improvement was sustained in the long term (9-10 years) in patients who continued therapy. |
| 4.2 | Cost effectiveness |
| 4.2.1 | One economic evaluation and three cost studies were identified. The only economic evaluation was reported in an outdated Wessex Development and Evaluation Committee (DEC) report (No. 47, 1995), which had subsequently been replaced by another Wessex DEC report (No. 75, 1997). The latter did not present an economic analysis. The utility element of the economic evaluation presented in the earlier DEC report was a set of scenarios not based on primary or secondary data sources and thus could not be considered reliable or valid. |
| 4.2.2 | The three cost studies identified were UK-based. One reported cost of diagnosis, GH treatment, and monitoring. The others reported drug costs. All studies reported the cost of the drug as the main factor determining treatment cost (around 90% of total cost). One study reported that annual treatment costs per patient could vary between £3472 and £6943 (1997 prices and GH dose from 0.125 to 0.25 IU/kg/week), and that costs were sensitive to assumptions about continuation rate and the price of GH. The other two studies reported annual drug costs of GH treatment in the range £3300 to £3453, using more up-to-date (median) drug doses. |
| 4.2.3 | A cost analysis was presented in the Wessex Assessment Report with the aim of analysing the average total lifetime and annual costs of GH treatment for a patient starting treatment. There was no attempt to estimate the cost effectiveness (or the cost-utility) of GH treatment. The Assessment Group considered that it was not possible to estimate utility gain - which would ideally be expressed in terms of quality-adjusted life years (QALYs) - with the evidence available from RCTs, and so the analysis was limited to costs. It was estimated that GH treatment in GH-deficient adults costs £3424 annually at an average maintenance dose. The costs of life-long therapy are estimated to be between £42,000 (adult-onset GH deficiency) and £45,400 (childhood-onset GH deficiency) without the cost-savings from hospitalisations prevented, and between £40,500 (adult-onset GH deficiency) and £43,800 (childhood-onset GH deficiency) with the savings from hospitalisations prevented. These estimates assume that 20% of people discontinue GH after 6 months' treatment. |
| 4.2.4 | Drug therapy was found to be the single most important factor in determining cost; changes in the price of GH significantly altered treatment costs, and thus any potential for price reductions could result in cost savings for the NHS. It was also noted that the price at local level could significantly differ from the BNF list price but there were no reliable data to inform the analysis. |
| 4.2.5 | Three manufacturers submitted economic evaluations to the Institute; all three estimated the cost-utility of GH use in adults (that is, they expressed the benefits of treatment in terms of QALYs). One also expressed cost effectiveness in the form of cost per normalised life-year gained. |
| 4.2.6 | Two economic models (Lilly and Novo Nordisk) adopted the methods used in the Wessex DEC report to generate utility estimates. The cost-utility ratios estimated by these models were between £4500 and £32,000 per additional QALY gained. These models did not use primary data, but were based on estimates of the likely utility gains for which there is little evidence. The models should therefore be treated with caution. |
| 4.2.7 | One manufacturer's model estimated the cost effectiveness to be £15,648 per additional normalised life-year for adult-onset GH deficiency and £16,522 per additional normalised life-year for childhood-onset GH deficiency. The data come from pre- and post-treatment scores of 124 UK patients using the questions on life satisfaction modules for hypopituitarism questionnaire (QLS?H) - a new QoL instrument for adults with GH deficiency, which covers nine domains. 'Normalisation' of QoL was defined as achieving a 'somewhat satisfied', 'satisfied' or 'very satisfied' score in all domains. |
| 4.2.8 | Another manufacturer's model estimated the cost effectiveness of the use of GH replacement therapy in adults to be between £27,500 and £37,600 per additional QALY gained. This model also used some inputs (especially those related to cardiovascular and fracture risks) derived from a simulation model, which was also provided. Utility estimates were derived from QoL data collected in the KIMS database. As the QoL-AGHDA questionnaire is not designed to produce preference-based utilities, regression analysis was used to convert the available data into utility scores. Sub-group analyses for different age and QoL groups were also presented. It should be noted that the use of regression analysis to derive the utility scores is limited by the quality of the data from which they are estimated and the degree of overlap of the descriptive systems. |
| 4.2.9 | The economic analysis presented by ScHARR demonstrated that the long-term effects on risk factors for fractures and cardiovascular events had very little impact on the cost effectiveness of GH treatment. The ScHARR report also included a series of sensitivity analyses to investigate the impact on the results of relaxing the assumptions used by the manufacturers, which were regarded as optimistic. |
| 4.2.10 | The ScHARR estimate of the impact of GH treatment on QoL was based on the use of observational data using the QoL-AGHDA questionnaire. This was regarded as an optimistic scenario because observational data are very prone to overestimate the treatment effect, particularly for subjective outcomes for which the placebo effect may be especially problematic. A similar mapping exercise to that used in one of the manufacturer's analyses (see Section 4.2.8) was used to derive the utility scores. Additional QoL data, made available to ScHARR by one of the manufacturers, measured the benefits by using the QLS-H questionnaire, but there is currently no method to map these findings to utility scores. |
| 4.2.11 | The ScHARR analysis, based on an overall utility gain of 0.04 to 0.12 depending on age and baseline QoL score, estimated the cost effectiveness of GH therapy to be between £25,300 (for people aged 65 years or older with a QoL-AGHDA score = 16) and £124,950 (for people aged 18-30 years with a QoL-AGHDA score of 6-10). The overall cost effectiveness of GH therapy is estimated to be in the region of £45,000 per additional QALY. This figure is very sensitive to the estimate of effectiveness, and it should be regarded as the best-case, most optimistic scenario as it is based on observational data that are likely to overestimate the benefits of treatment. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Committee reviewed the evidence available on the clinical and cost effectiveness of GH treatment in adults with GH deficiency, having considered evidence on the nature of the condition and the value placed by users on the benefits of GH treatment from adults with GH deficiency, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. |
| 4.3.2 | The Committee considered in detail the significance of the effectiveness of GH treatment in GH-deficient adults in respect of its effects on QoL. In addition, the Committee considered the potential effect of GH deficiency on clinical parameters that might adversely affect cardiovascular risk profiles and the potential for bone fractures caused by reduced bone mineral density, both of which in turn might adversely affect life expectancy. The possibility that GH deficiency might also contribute to a lower overall standardised mortality ratio (SMR), over and above that which can be attributed to the effects on cardiovascular risk and that related to reduction in bone mineral density, was also taken into account. |
| Effects of HGH replacement on quality of life | |
| 4.3.3 | The Committee considered that improvement in QoL was an important, if not the only, determinant of the clinical and cost effectiveness of GH treatment. They therefore considered at length the assessment tools for QoL used in studies of GH therapy, and in particular the appropriateness and suitability of the NHP, QLS-H, EQ-5D and QoL-AGHDA scoring systems. In addition, the Committee reviewed the evidence on QoL effects from both the RCTs and the observational studies. The Committee was also aware of the high compliance rates among GH users (reported to be around 92%), as pointed out by both the patient representatives and experts. |
| 4.3.4 | It was acknowledged that there were inconsistencies between the results of RCTs, observational studies and the accounts of many individual patients about the effect of GH therapy on QoL. The Committee took into account the deficiencies in the evidence from RCTs. In particular, the Committee considered the possibility that a sub-group of patients - those with very poor QoL - were benefiting from treatment, but that the effect in these patients was obscured by the inclusion of a large proportion of patients with relatively good pre-treatment QoL and hence little scope for improvement. |
| 4.3.5 | During the course of this appraisal, the Committee was presented with several analyses relating to improvement in QoL (in addition to original submissions) that attempted to identify a subgroup of patients in whom GH therapy would be cost effective (that is, those who would gain an improvement in QoL much larger than the average improvements seen in RCTs and observational studies). The Committee reviewed data from an updated subgroup analysis based on a postal survey of 197 people with HGH deficiency using the EQ-5D questionnaire. This re-analysis suggested that improvement in utility due to GH treatment might be up to 40% greater than that estimated by QoL-AGHDA. The Committee also reviewed additional data based on QLS-H assessments (from the Hypopituitary Control and Complication Study [HypoCCS] database). The results from this analysis confirmed that there was likely to be a subgroup of people with HGH deficiency who would gain significantly greater improvements in QoL on HGH replacement. However, it was not possible to map the data from QLS-H scores into utilities, and hence this did not provide further direct information to inform the analysis of the cost effectiveness of this technology for selected subgroups. |
| 4.3.6 | The Committee accepted that, although there was not sufficient information available to them to enable a detailed evaluation of the quality of the methods used to derived the new EQ-5D data, a greater degree of utility change using EQ-5D in comparison with the QoL-AGHDA would be anticipated in view of the well-established differences in the properties of these two QoL tools. The Committee considered that these additional data suggested that an improvement of the order of 7 points in QoL?AGHDA score from baseline would be needed to achieve an acceptable level of cost effectiveness. |
| Effects of GH replacement on mortality | |
| 4.3.7 | The Committee considered in detail the effect of GH replacement on overall mortality from various causes in people with GH deficiency. They considered the potential deleterious effects on cardiovascular risk profiles and bone mineral density as well as data on SMRs for people with GH deficiency compared with matched populations. The Committee noted that the association between increased mortality and GH deficiency was based on uncontrolled, observational data and on the assessment of cohorts from different periods. |
| 4.3.8 | The Committee concluded that it was uncertain what impact GH treatment had on the longer-term clinical outcomes and mortality related to the impact on cardiovascular risk factors and changes in bone mineral density. However the Committee believed that the best available evidence from observational studies of these risk factors on mortality had been included in the overall estimates of cost effectiveness that it had reviewed. The Committee considered that it was problematic to draw conclusions about the impact of isolated GH deficiency on overall SMRs (that is, mortality over and above that attributable to cardiovascular risk and bone mineral density changes), as the populations reported in different studies were heterogeneous, which made comparisons difficult. In addition, the SMR data were not adjusted for potential confounding factors, and causality could not be clearly explained. |
| Summary of considerations for adult-onset GH deficiency | |
| 4.3.9 | The Committee was persuaded that there was a subgroup of people with GH deficiency whose QoL was significantly impaired and for whom the benefits of GH replacement would be both clinically and cost effective. However, the additional benefit of treatment on overall mortality was less certain and, on the basis of the present evidence, was likely to have been accounted for predominantly by taking into account effects on cardiovascular risk profiles. While accepting that other factors directly or indirectly affecting overall mortality may be present in GH-deficient people, the Committee believed that these would need to be explored in future research. |
| 4.3.10 | The Committee reviewed the analyses of cost effectiveness of GH replacement in adult-onset GH deficiency, including the updated analysis submitted by one manufacturer, which assessed in detail the various factors that might influence the calculations of incremental cost-effectiveness ratios (ICERs), including QoL utility estimates based on different methodologies, the potential effects on overall mortality and the appropriateness of modelling benefits over different time horizons. |
| 4.3.11 | After reviewing the updated cost-effectiveness analyses, and the data from the KIMS database on the levels of improvement (in terms of QoL-AGHDA scores) for different patient groups, the Committee considered that the subgroup of people with GH deficiency for whom treatment would be cost effective would be those who had a benefit from improvement in QoL equivalent to an absolute change in their baseline QoL-AGHDA score of the order of 7 points. The Committee considered that the ICER for this group of patients would be in the region of £25,000 to £45,000 per QALY. |
| 4.3.12 | The Committee accepted that, for the normal population, the baseline QoL-AGHDA score should be taken as 2-4. Therefore, on this basis and taking into account the consideration in Section 4.3.10, the Committee considered that the baseline QoL-AGHDA score at which treatment should be initiated should be 11 or greater. This was supported by the data from the KIMS database, which showed that this level of improvement (7 points) was only documented in patients with a baseline QoL-AGHDA score of 11 or over. |
| 4.3.13 | Therefore, the Committee concluded that the use of GH treatment could be recommended for people with GH deficiency, and with a severe perceived impairment of QoL as demonstrated by a reported score of at least 11 in QoL-AGHDA. Re-assessment of the need for HGH replacement should then take place after a trial period of 9 months (3 months' dose titration and 6 months' assessment). For GH treatment to continue after this trial period, it should be necessary to demonstrate a sustained QoL improvement of at least 7 points in QoL-AGHDA score compared with the baseline measurement. |
| Transitional period | |
| 4.3.14 | The Committee considered the issues related to the treatment arrangements for those with childhood-onset GH deficiency from all causes, and the value of GH treatment above and beyond the completion of linear growth. It was agreed that people with childhood-onset GH deficiency should be re-jtested after the attainment of final height to assess whether they are eligible for further GH replacement (see Section 1.1). |
| 4.3.15 | The Committee was persuaded by evidence from experts that, for people with childhood-onset GH deficiency who had completed linear growth but still remained severely deficient in GH on the basis of biochemical tests, treatment with GH should be continued until adult bone mass is achieved. The Committee accepted that there are likely to be significant disadvantages in later life for those who do not achieve peak adult bone mass, although this conclusion was not fully evidence-based. The Committee additionally accepted, on the basis of expert testimony, that the age at which peak adult bone mass is achieved may vary between 25 and 30 years depending on a number of factors, including the age of puberty. |
| 4.3.16 | The Committee concluded, therefore, that there will be a proportion of people with childhood-onset GH deficiency for whom continuation of treatment until peak adult bone mass is achieved is desirable. Thereafter, GH treatment should be discontinued and only recommenced on the basis of the criteria laid down for adult-onset GH deficiency (see Section 1.1). |
| 5 | Proposed recommendations for further research |
| 5.1 |
Further good-quality studies are needed in the following areas.
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| 6 | Preliminary views on the resource impact for the NHS |
| This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible. | |
| 6.1 | Although it is hard to estimate the number of eligible patients accurately, it is anticipated that only a small proportion of adults with GH deficiency will achieve sustained improvement of at least 7 points on the QoL-AGHDA scale at the end of the assessment period (that is, 9 months). If it is assumed that 30% of adult-onset and 15% of childhood-onset patients will fulfil this criterion, there will be around 2350 people in England and Wales who would be eligible for continuous GH treatment. This would equate to an annual cost of around £8 million to the NHS. However, considering that there are currently 1750 adult patients already receiving GH treatment, the additional cost to the NHS would be in the region of £2 million per year. |
| 7 | Proposals for implementation and audit |
| This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1. | |
| 7.1 | Clinicians who provide care for adults with GH deficiency should review policies and practices regarding the prescription of GH in adults to take account of the guidance set out in Section 1. |
| 7.2 | Local guidelines or care pathways on the treatment of adults with GH deficiency should incorporate the guidance set out in Section 1. |
| 7.3 | To measure compliance locally with the guidance, the following criteria can be used. Further details on suggestions for audit are presented in Appendix C. |
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7.3.1
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Recombinant human growth hormone (somatropin) treatment is given to an adult with GH deficiency only if he or she meets all three of the criteria 7.3.1.1-7.3.1.3 or criterion 7.3.1.4. |
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7.3.1.1
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The individual has severe GH deficiency, defined as having a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test (ITT) or a cross-validated GH threshold in an equivalent test. |
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7.3.1.2
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The individual has a perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific 'QoL-assessment of growth hormone deficiency in adults (QoL-AGHDA)' questionnaire. |
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7.3.1.3
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The individual is already receiving full replacement with other deficiency pituitary hormones as required. |
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7.3.1.4
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The individual is currently receiving GH treatment at the date of publication of this guidance and following re-assessment by his or her consultant endocrinologist, as part of routine follow-up, it is considered appropriate to continue the therapy taking into account the guidance in Section 1. |
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7.3.2
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An adult who is being started on GH treatment is re-assessed for QoL status 9 months after the initiation of therapy and GH treatment is discontinued if the individual has a QoL improvement of less than 7 points in QoL-AGHDA score. |
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7.3.3
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For an individual who as a child has been treated for GH deficiency and who has completed linear growth, the following are done. |
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7.3.3.1
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GH treatment is stopped for 2-3 months. |
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7.3.3.2
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The GH status of the individual is re-assessed. |
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7.3.3.3
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GH treatment at an adult dose is re-started only if the individual has a peak GH response of less than 9 mU/litre (3 ng/ml) during an ITT, or a cross-validated GH threshold in an equivalent test. |
|
7.3.3.4
|
GH treatment at an adult dose is continued until adult peak bone mass is achieved. |
|
7.3.3.5
|
When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 7.3.1.1-7.3.1.3. |
|
7.3.4
|
The following are carried out only by a consultant endocrinologist with a special interest in the management of disorders of GH.
|
|
7.3.5
|
If maintenance GH treatment is to be prescribed in a primary care setting, there is an agreed shared-care protocol. |
| 8 | Related guidance |
| 8.1 |
The Institute issued guidance in May 2002 on the use of GH treatment in children with growth failure.
|
| 9 | Proposed date for review of guidance |
| 9.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. |
| 9.2 | It is proposed that the guidance on this technology is reviewed in June 2006. |
| Professor David Barnett |
| Chairman, Appraisal Committee |
| February 2003 |
| Appendix A. Appraisal Committee members |
|
NOTE 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 other than 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 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 Tom Aslan |
| General Practitioner, Stockwell, London |
| Professor David Barnett (Chair) |
| Professor of Clinical Pharmacology, University of Leicester |
| Professor Sir Colin Berry (term of office ended October 2002) |
| Retired Professor of Morbid Anatomy & Histopathology, The Royal London Hospital |
| Dr Sheila Bird |
| MRC Biostatistics Unit, Cambridge |
| Professor Rosamund Bryar |
| Professor of Community & Primary Care Nursing, St Bartholomew's School of Nursing & Midwifery, London |
| Dr Karl Claxton |
| Health Economist, University of York |
| Dr Richard Cookson |
| Senior Lecturer, Health Economics, School of Health Policy and Practice, University of East Anglia, Norwich |
| Professor Sarah Cowley (term of office ended October 2002) |
| Professor of Community Practice Development, Kings College, London |
| Professor Nicky Cullum (up to January 2002) |
| Professor in Health Sciences/Director, Centre for Evidence-based Nursing, University of York |
| Mr Chris Evennett (up to June 2002) |
| Chief Executive, Mid-Hampshire Primary Care Trust, Winchester |
| Professor Terry Feest |
| Clinical Director & Consultant Nephrologist, Richard Bright Renal Unit, & Chair of UK Renal Registry, Bristol |
| Professor Gary A Ford |
| Professor of Pharmacology of Old Age/Consultant Physician, Newcastle upon Tyne Hospitals NHS Trust |
| Ms Jean Gaffin (up to February 2002) |
| Formerly Executive Director National Council for Hospice and Specialist Palliative Care Service |
| Mrs Sue Gallagher (term of office ended October 2002) |
| Former Chief Executive, Merton, Sutton & Wandsworth Health Authority, London |
| Ms Bethan George |
| Interface Liaison Pharmacist, Tower Hamlets PCT and Royal London Hospital, Whitechapel |
| Dr Trevor Gibbs |
| Head, Global Clinical Safety & Pharmacovigilance, GlaxoSmithKline, Greenford |
| Mr John Goulston |
| Director of Finance, St Bartholoemew's Hospital & the London NHS Trust |
| Dr Terry John |
| General Practitioner, The Firs, London |
| Dr Diane Ketley (term of office ended August 2002) |
| Research into Practice Programme Leader, NHS Modernisation Agency, Leicester |
| Dr Mayur Lakhani (term of office ended August 2002) |
| General Practitioner, Highgate Surgery, Leicester, & Lecturer, University of Leicester |
| Mr Muntzer Mughal |
| Consultant Surgeon, Lancashire Teaching Hospitals NHS Trust, Chorley |
| Mr James Partridge |
| Lay Representative; Chief Executive, Changing Faces, London |
| Mrs Kathryn Roberts |
| Nurse Practitioner, Hyde, Cheshire |
| Professor Philip Routledge |
| Professor of Clinical Pharmacology, College of Medicine, University of Wales, Cardiff |
| Ms Anne Smith |
| Consultant (Management) and Trustee of the Long-Term Medical Conditions Alliance |
| Professor Andrew Stevens (Vice-Chair) |
| Professor of Public Health, University of Birmingham |
| Dr Cathryn Thomas |
| General Practitioner, & Senior Lecturer, Department of Primary Care & General Practice, University of Birmingham |
| Dr Norman Vetter |
| Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff |
| Dr David Winfield |
| Consultant Haematologist, Royal Hallamshire Hospital, Sheffield |
| Appendix B. Sources of evidence considered by the Committee | |
| The assessment reports for this appraisal were prepared by: | |
| A. |
1) Southampton Health Technology Assessment Centre, University of Southampton
2) School of Health and Related Research (ScHARR), University of Sheffield
|
| B. |
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 ACD and consultee organisations are provided with the opportunity to appeal against the FAD. 1) Manufacturers/sponsers:
2) Professional/specialist and patient/carer groups:
|
| C. |
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 human growth hormone (somatropin) in adults with growth hormone deficiency by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.
|
| Appendix C. Detail on criteria for audit of the use of human growth hormone (somatropin) in adults with growth hormone deficiency | |||
| Possible objective for an audit | |||
|
An audit on the appropriateness and effectiveness of use of growth hormone (GH) treatment in adults with GH deficiency could be carried out to ensure the following.
|
|||
| Possible patients to be included in the audit | |||
| An audit could be carried out on all adults referred or seen for GH deficiency in a given time period, for example, 6 months or a year. Because the measures listed below refer to care provided after the start of GH treatment, it may be desirable to limit the audit to new patients or to agree on the specific time period of care that will apply to each of the measures. | |||
| Measures that could be used as a basis for an audit | |||
| The measures that could be used in an audit of GH treatment are as follows. |
|
Criterion
|
Standard
|
Exception
|
Definition of Terms
|
|
1. An adult given recombinant human growth hormone meets all three of a-c or d as follows: a. The individual has severe GH deficiency and |
100% of the adults who are on recombinant human growth hormone | None |
Recombinant human growth hormone = somatropin. Severe GH deficiency = having a peak GH response of less than 9 mU/litre (less than 3 ng/ml) during an insulin tolerance test (ITT) or a cross-validated GH threshold in an equivalent test. See the individual's self-reported score on the QoL-AGHDA questionnaire.For d, 're-assessment' = by the individual's consultant endocrinologist as part of routine follow-up. For d, 're-assessment' = by the individual's consultant endocrinologist as part of routine follow-up. For d, 'appropriate to continue' assumes that the consultant considers the criteria stated in 1a-1c. Clinicians will have to agree locally on how consideration of the appropriateness of continuation of therapy, for patients on GH therapy at the date of publication of this guidance, is documented for audit purposes. |
|
2. An adult who is started on GH treatment: a. Is re-assessed for QoL status 9 months after the initiation of therapy b. Has GH treatment discontinued if the individual has a QoL improvement of less than 7 points in QoL-AGHDA score |
100% of the adults started on GH treatment within the time period agreed for audit purposes 100% of the adults with insufficient QoL improvement |
None None |
Clinicians will have to agree locally how far back in time care is to be reviewed for this criterion, and on where QoL status at 9 months after initiation of therapy will be documented for audit purposes, ie, where the QoL-AGHDA questionnaire scores are ordinarily recorded. 9 months after the initiation of therapy = an initial 3-month period of GH dose titration followed by a 6-month therapeutic trial period. |
|
3. The following are done for an individual who as a child has been treated for GH deficiency and who has completed linear growth: a. GH treatment is stopped for 2-3 months b. The GH status of the individual is reassessed c. GH treatment at an adult dose is re-started only if the individual meets criterion 1a aboved. GH treatment at an adult dose is continued until adult peak bone mass is achieved d. GH treatment at an adult dose is continued until adult peak bone mass is achieved e. When adult peak bone mass is achieved, GH treatment is continued only if the individual meets criteria 1a-1c above |
For 3 a and b:100% of the individuals who have been treated for GH deficiency and who have completed linear growth
For 3 e: 100% of the individuals who achieve adult peak bone mass and who have GH treatment continued |
For 3 a and b: None
For 3 e: None |
Completion of linear growth = rate <2cm/year. Adult peak bone mass is normally achieved by about 25 years of age. Re-assessed = for GH status and QoL as defined in 1 above. |
|
4. The following are carried out by a qualified specialist: a. Initiation of GH treatment and |
100% of the individuals who are given GH therapy | None |
A qualified specialist is a consultant endocrinologist with a special interest in the management of disorders of GH. Clinicians will have to agree locally how far back in time care is to be reviewed for this criterion. |
| 5. If an individual's maintenance GH treatment is prescribed in a primary care setting, there is an agreed shared-care protocol | 100% of individuals seen for maintenance prescription in a primary care setting | None | Clinicians will have to agree locally on what constitutes agreement on a shared-care protocol |
| Calculation of compliance with the measure | ||
| Compliance (%) with each measure described in the table above is calculated as follows. | ||
|
Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed |
||
|
|
X 100 | |
|
Number of patients to whom the measure applies |
||
| Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved. | ||
This page was last updated: 30 March 2010