A will and a way to fund medicines for rare diseases: the story of human growth hormone replacement for adults with growth hormone deficiency.

Growth hormone (GH) replacement therapy was recently recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme for adults with severe GH deficiency and impaired quality of life. This approval was significant for two reasons. First, the application was initiated and coordinated by a health professional working group, who prepared a 'public interest' submission to PBAC. Second, it resulted in a recommendation to subsidise therapy for a rare disease after two prior rejections on the basis of uncertainty about efficacy and cost effectiveness. There are important lessons to learn about the power of professional groups to drive health policy and attain funding for rare diseases.

Extensive expertise in endocrinology: UK stance on adult GH replacement: the economist vs the endocrinologist.

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

An analysis of the clinical and cost effectiveness of growth hormone replacement therapy before and during puberty: should we increase the dose?

AIM: To investigate the influence of growth hormone (GH) on linear growth before and during puberty in children with GH deficiency. METHODS: We analysed the relationship between pubertal growth and GH dose in a large dataset of children (n = 236) with GH deficiency using multiple linear regression and multilevel modelling with repeated measures analysis. Additionally, we examined the cost benefit of increasing doses of GH during puberty. RESULTS: Multilevel modelling revealed a highly significant role for GH dose in the pre-pubertal period (p < 0.001), but a non-significant effect on height gain after pubertal onset (p = 0.32). Important predictors of height gain after puberty onset included gender, age at puberty and number of injections of GH/week. Cost analysis showed that in an average child use of high dose GH, at an extra EUR 5,925 (GBP 4,753/USD 7,538)/year, would produce a height gain of 0.80 cm/year (above baseline growth) pre-pubertally, compared to only 0.20 cm/year post-puberty onset. CONCLUSIONS: The influence of GH dose on height gain after puberty onset is at best a modest one. Cost analysis shows use of high doses of GH post-puberty onset has significant cost implications without providing a worthwhile gain in adult height for children with GH deficiency.

Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.

BACKGROUND: Recombinant human growth hormone (rhGH) is licensed for short stature associated with growth hormone deficiency (GHD), Turner syndrome (TS), Prader-Willi syndrome (PWS), chronic renal insufficiency (CRI), short stature homeobox-containing gene deficiency (SHOX-D) and being born small for gestational age (SGA). OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of rhGH compared with treatment strategies without rhGH for children with GHD, TS, PWS, CRI, SHOX-D and those born SGA. DATA SOURCES: The systematic review used a priori methods. Key databases were searched (e.g. MEDLINE, EMBASE, NHS Economic Evaluation Database and eight others) for relevant studies from their inception to June 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers, and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. Quality of included studies was assessed using standard criteria, applied by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through a narrative review. RESULTS: Twenty-eight randomised controlled trials (RCTs) in 34 publications were included in the systematic review. GHD: Children in the rhGH group grew 2.7 cm/year faster than untreated children and had a statistically significantly higher height standard deviation score (HtSDS) after 1 year: -2.3 ± 0.45 versus -2.8 ± 0.45. TS: In one study, treated girls grew 9.3 cm more than untreated girls. In a study of younger children, the difference was 7.6 cm after 2 years. HtSDS values were statistically significantly higher in treated girls. PWS: Infants receiving rhGH for 1 year grew significantly taller (6.2 cm more) than those untreated. Two studies reported a statistically significant difference in HtSDS in favour of rhGH. CRI: rhGH-treated children in a 1-year study grew an average of 3.6 cm more than untreated children. HtSDS was statistically significantly higher in treated children in two studies. SGA: Criteria were amended to include children of 3+ years with no catch-up growth, with no reference to mid-parental height. Only one of the RCTs used the licensed dose; the others used higher doses. Adult height (AH) was approximately 4 cm higher in rhGH-treated patients in the one study to report this outcome, and AH-gain SDS was also statistically significantly higher in this group. Mean HtSDS was higher in treated than untreated patients in four other studies (significant in two). SHOX-D: After 2 years' treatment, children were approximately 6 cm taller than the control group and HtSDS was statistically significantly higher in treated children. The incremental cost per quality adjusted life-year (QALY) estimates of rhGH compared with no treatment were: 23,196 pounds for GHD, 39,460 pounds for TS, 135,311 pounds for PWS, 39,273 pounds for CRI, 33,079 pounds for SGA and 40,531 pounds for SHOX-D. The probability of treatment of each of the conditions being cost-effective at 30,000 pounds was: 95% for GHD, 19% for TS, 1% for PWS, 16% for CRI, 38% for SGA and 15% for SHOX-D. LIMITATIONS: Generally poorly reported studies, some of short duration. CONCLUSIONS: Statistically significantly larger HtSDS values were reported for rhGH-treated children with GHD, TS, PWS, CRI, SGA and SHOX-D. rhGH-treated children with PWS also showed statistically significant improvements in body composition measures. Only treatment of GHD would be considered cost-effective at a willingness-to-pay threshold of 20,000 to 30,000 pounds per QALY gained. This analysis suggests future research should include studies of longer than 2 years reporting near-final height or final adult height.

The cost-effectiveness of somatropin treatment for short children born small for gestational age (SGA) and children with growth hormone deficiency (GHD) in Sweden.

OBJECTIVE: Reduction in health-related quality of life is common in children born small for gestational age (SGA) or children with growth hormone deficiency (GHD). Growth hormone treatment with somatropin in these children leads to normalisation of height. The aim of this study was to determine whether somatropin is a cost-effective treatment option for short children born SGA and GHD children in Sweden. METHODS: A Markov decision-tree model was used to calculate the relative costs and health benefits associated with somatropin treatment over the lifetime of SGA and GHD children, compared with no treatment. The analysis was undertaken from a Swedish Health Service perspective. As quality-adjusted life-year (QALY) data were not obtained directly in the clinical studies, a degree of uncertainty is related to these results. Sensitivity analyses assessed the degree of uncertainty surrounding central parameters. RESULTS: For short children born SGA, somatropin treatment was associated with an additional 3.29 QALYs at an incremental cost of 792,489 SEK (Swedish Krona), compared with no treatment. For GHD, somatropin treatment resulted in 3.25 additional QALYs at an incremental cost of 391,291 SEK. This equates to an incremental cost per QALY of 240,831 SEK and 120,494 SEK for SGA and GHD, respectively, below a cost-effectiveness threshold of 500,000-600,000 SEK/QALY. CONCLUSIONS: Somatropin is a cost-effective treatment strategy in Sweden for children with GHD and SGA. To overcome present study limitations future clinical research should incorporate appropriate quality of life questionnaires.

Cost-utility of somatropin (rDNA origin) in the treatment of growth hormone deficiency in children.

OBJECTIVE: The objective of this study was to generate estimates of cost-effectiveness/utility of somatropin (rDNA origin) in the treatment of growth hormone deficiency (GHD) in children. METHODS: A decision-analytic model of the epidemiology and treatment of GHD in children was developed. Treatment of GHD was assessed in two hypothetical cohorts compared to no treatment--treatment with somatropin 0.030 mg/kg/day from ages 5 to 16 years, and treatment from ages 3 to 18 years. Costs (stated in 2005 US$) included those related to drug acquisition, endocrinologist consultations, and primary care office visits. Estimates of patient weight by age and sex were derived from published literature, as was the proportion of patients achieving normal height through somatropin treatment and pre/post-treatment patient utilities. Cost-effectiveness/utility was estimated over patients' expected lifetimes, and was stated alternatively as discounted (3% per annum) US dollars per normal height year (NHY) gained, and cost per quality adjusted life-year (QALY) gained. Multivariate sensitivity analyses were conducted to ensure robustness of the model. RESULTS: The cost-effectiveness and cost-utility of treating children from ages 5 to 16 years with somatropin was estimated at approximately $8,900 per NHY gained and $37,000 per QALY gained, respectively. Corresponding ratios pertaining to treatment of children from ages 3 to 18 years were $9,300 per NHY gained and $42,600 per QALY gained. Findings were relatively insensitive to variation in most model parameters. CONCLUSIONS: For both age cohorts, the cost-effectiveness/utility of somatropin in the treatment of GHD compares favorably to well-accepted threshold values. The use of somatropin represents reasonable value for money for the treatment of GHD in children.