Growth hormone prescribing and initial BMI SDS: Increased biochemical adverse effects and costs in obese children without additional gain in height.

BACKGROUND: Recombinant human growth hormone (rhGH) treatment in children is usually prescribed using actual body weight. This may result in inappropriately high doses in obese children. METHODS: Retrospective audit of all paediatric patients treated with rhGH 2010-14 at a tertiary paediatric hospital in the UK. Change in height SDS and IGF-I SDS during the first year of treatment was stratified by initial BMI SDS in a mixed cohort, and a subgroup of GH deficient (GHD) patients. Alternative doses for those BMI SDS ≥2.0 (Obese) were calculated using BSA, IBW and LBW. RESULTS: 354 patients (133 female) received rhGH, including 213 (60.2%) with GHD. Obesity was present in 40 patients (11.3%) of the unselected cohort, and 32 (15.0%) of the GHD cohort. For GHD patients, gain in height SDS was directly related to BMI SDS, except in obese patients (p<0.05). For both the entire cohort, and GHD patients only, IGF-1 SDS was significantly higher in obese patients (p<0.0001 for both groups). Cross sectional data identified 265 children receiving rhGH, 81 (30.5%) with a BMI-SDS ≥1.75. Alternate prescribing strategies for rhGH prescribing in obese patients suggest a saving of 27% - 38% annually. CONCLUSIONS: Gain in IGF-I SDS is greater in obese children, and is likely to be related to relatively higher doses of rhGH. Additional gain in height was not achieved at the higher doses administered to obese children. Alternative dosing strategies in the obese patient population should be examined in rigorous clinical trials.

The effect of bovine somatotropin on the cost of producing milk: Estimates using propensity scores.

Annual farm-level data from New York dairy farms from the years 1994 through 2013 were used to estimate the cost effect from bovine somatotropin (bST) using propensity score matching. Cost of production was computed using the whole-farm method, which subtracts sales of crops and animals from total costs under the assumption that the cost of producing those products is equal to their sales values. For a farm to be included in this data set, milk receipts on that farm must have comprised 85% or more of total receipts, indicating that these farms are primarily milk producers. Farm use of bST, where 25% or more of the herd was treated, ranged annually from 25 to 47% of the farms. The average cost effect from the use of bST was estimated to be a reduction of $2.67 per 100 kg of milk produced in 2013 dollars, although annual cost reduction estimates ranged from statistical zero to $3.42 in nominal dollars. Nearest neighbor matching techniques generated a similar estimate of $2.78 in 2013 dollars. These cost reductions estimated from the use of bST represented a cost savings of 5.5% per kilogram of milk produced. Herd-level production increase per cow from the use of bST over 20 yr averaged 1,160 kg.

[Can we transfer the mechanisms of the generics market to biosimilars?]

Personalized medicines such as biologics and their generic equivalents, biosimilars, are pouring onto the pharmaceutical markets. Data of 16 private health insurance companies were used to describe the market shares of selected biosimilars available in 2014 and 2015. The purpose of this study focuses on the question of whether market access of biosimilars will lead to a price competition of the expense of innovation competition. The results show that prescriptions of biosimilars made up 37% of total prescriptions in 2015 compared to 35% in 2014, and that their share of prescription costs went up from 21% to 23% in the same period. Price competition similar to that found in the generic markets has been established for erythropoietin and filgrastim. The same has not been observed for follitropin alfa and somatropin due to the limited number of competitors and products available at this stage. No definitive conclusions can be drown from the results at this stage. Time will tell whether it will be possible for physicians and individuals with private health insurance to fully leverage the savings potential of biosimilars while safeguarding patient safety.

Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential.

OBJECTIVE: The combination therapy of gonadotropin-releasing hormone analogues (GnRHa) and recombinant human growth hormone (rhGH) has been used to increase growth in children with premature sexual maturation and attenuated growth. The aim of this report was to study the benefit over cost of combined treatment in girls with central precocious puberty (CPP) and poor height prognosis and in girls with idiopathic short stature (ISS) and early puberty. Should this expensive treatment be given to such patients? SUBJECTS AND METHODS: Two patient groups were included: five girls with central precocious puberty (CPP) who reached final height (FH) at 16.3±1.2 years and eight girls with ISS who reached FH at 14.7±0.8 years. Patients were treated for 3.5±0.6 years. RESULTS: In both groups, FH improved significantly; in CPP from -1.3 to -0.5 standard deviation score (SDS) (p=0.030) and in ISS from -2.6 to -1.7 SDS (p=0.012). Only girls with CPP reached their target height (-0.5 vs. -0.6 SDS) (p=0.500). CONCLUSIONS: Both groups had a total height gain of 5 cm. Each centimetre cost about €2700 per patient. This treatment should be considered only in patients with extremely low height prediction and very early pubertal onset.

Dealing with moral dilemma raised by adaptive preferences in health technology assessment: the example of growth hormones and bilateral cochlear implants.

The aim of this article is to assess dilemma raised by adaptive preferences in the economic evaluation of growth hormone (GH) treatment for non-GH-deficient short children, and of bilateral cochlear implants for deaf children. Early implementation of both technologies and their irreversible consequences increase the potential conflicts faced by the assessors of health-related quality of life (HRQoL) states (on behalf of patients) who could be interviewed (parents, individuals with an experience of the same disability, or representative samples of the general public). Indeed, assessors' preferences may be influenced by their own situation and they are likely to vary according to age and the experience of disability. Three options are put forward which aim to resolve these moral dilemma and help economists make methodological choices that cannot be avoided in order to carry out this assessment. They are grounded on three specific egalitarian theories of social justice. The main contribution of this article is to show that a dialogue between ethics and economics, prior to an assessment, makes it possible to redefine the choice of effectiveness criteria (subjective well-being, capabilities or social outcomes), the choice of perspective (patients or the able-bodied), as well as the scope of assessment (medical and non-medical care).

Internet informs parents about growth hormone.

BACKGROUND: Parents' knowledge influences decisions regarding medical care for their children. METHODS: Parents of pediatric primary care patients aged 9-14 years, irrespective of height, participated in open focus groups (OFGs). Moderators asked the question, 'How do people find out about growth hormone (GH)?' Because many parents cited the Internet, the top 10 results from the Google searches of 'growth hormone children' and 'parents of children who take growth hormone' were examined. Three investigators independently performed content analysis and then reached a consensus. The results were tabulated via summary statistics. RESULTS: Eighteen websites were reviewed, most with the purpose of education (56%) and many funded by commercial sources (44%). GH treatment information varied, with 33% of the sites containing content only about US FDA-approved indications. Fifty-six percent of the sites included information about psychosocial benefits from treatment, with 44% acknowledging them as controversial. Although important to OFG participants, risks and costs were each omitted from 39% of the websites. CONCLUSION: Parents often turn to the Internet for GH-related information for their children, although its content may be incomplete and/or biased. Clinicians may want to provide parents with tools for critically evaluating Internet-based information, a list of prereviewed websites, or their own educational materials.

Developments in idiopathic short stature: cost versus allocation of resources.

In the context of health-care costs, containment and economic downturn, there is a question as to whether the high cost of growth hormone (GH) therapy for patients with idiopathic short stature (ISS) is worth the health benefit provided. The economic evaluations of GH for the treatment of patients with ISS have considered gain in height as the major clinical endpoint. The incremental cost of each centimetre of adult height gained due to GH treatment has been estimated to be between £13,500 and £27,200 (€16,400 to €33,100), but could range from £4,300 to £272,000 (€5,200 to €330,900) depending on height gain, GH dose and unit cost, as well as discount rate chosen. Evidence regarding a potential benefit on health-related quality of life is lacking.

SHOX mutation as a rare disease: molecular diagnosis and growth hormone treatment supported by the Italian public health system.

Short stature homeobox-containing (SHOX) gene deficiency is acknowledged under the term "dyschondrosteosis", which is included in the family of congenital osteodystrophies. Under current regulations, the cost of the genetic testing and treatment with GH in children with short stature, and SHOX gene deficiency may be reimbursed. Prescription of costs exemption is subject to the identification of the regional centers qualified to diagnose congenital osteodystrophies (RNG060). The centers qualified to diagnose and treat "dyschondrosteosis" have been identified in only a few regions, whereas in other regions centers for the diagnosis and treatment of congenital osteodystrophies have been identified, and in still others, no specific centers have been identified yet. Treatment with GH as indicated by European Medicines Agency (EMEA) for people with short stature and evidence of SHOX gene deficiency is governed by Agenzia Italiana del Farmaco (AIFA) note number 39. The latest version does not provide for the medication to be directly reimbursed by the National Health Service, although it may be prescribed for patients with well-defined auxological characteristics, subject to the prior authorization of the regional commission qualified to monitor the use of the GH. Therefore, a diagnostic/ therapeutic course for patients with short stature with SHOX gene mutation has been proposed. The healthcare course relating to such patients has not been thoroughly defined in terms of implementation and is affected by regional organizational approaches. Implementing specific healthcare courses for such patients may provide a model for treating other patients with short stature and rare diseases with GH.

[Therapy with recombinant growth hormone]. / Wachstumshormon bald auch bei Adipositas und Diabetes?

Therapy with recombinant growth hormone is currently approved for the indications growth hormone deficiency,Turner syndrome, chronic renal failure, small for gestational age (SGA) and Prader-Willi syndrome. Positive experience from on-going clinical studies (e.g. on obesity, type 2 diabetes, Crohn's disease) support an extended range of applications for recombinant growth hormone. However, growth hormone therapy is very expensive. On the other hand, biosimilars are already available that are significantly lower in price. During the coming years, research must show whether the efficacy and safety of biosimilars (including possible new indications) are equal to that of the established preparations.

Prioritisation by physicians in the Netherlands--the growth hormone example in drug reimbursement decisions.

Drug treatment and reimbursement is an area of ever growing complexity in health priority setting. This paper assesses the National Registry of Growth Hormone Treatment (LRG) responsible for making prioritisation decisions in the Dutch drug reimbursement system in the treatment of growth hormone, using the framework for fairness. We used qualitative research consisting of semi-structured interviews and focus group sessions combined with quantitative methods to audit the decisions of the forum. The rationing decisions of the forum demonstrate accountability for reasonableness by the conditions for transparency, relevance, and appeal. Most rationales for the decisions are public and transparent. The patients and paediatricians see decisions made by the LRG as clinical and therefore relevant decisions. They also refer to extensive appeal procedures. The case also raises important issues regarding the legitimacy of expert-based priority setting as the cyclic nature of guideline development conflicts with the need for maintaining strict rationing criteria. In 13% of the patients, the sick funds did cover treatment as the forum advised them to do, but according to guideline criteria it may be unlikely that these patients have growth hormone deficiency. According to the LRG, however, only 2% of the decisions are inconsistent with the guidelines, as some criteria on what to do in case of more uncertainty, shifted. For the forum, it seems rather unthinkable to go against the professional norms, in spite of formal national regulations. For the Health Care Insurance Board (CVZ), it was not considered possible to go against national regulations, especially as professional norms have shifted without informing policy makers and patient representatives.

Regulating of growth hormone sensitivity by sex steroids: implications for therapy.

Growth hormone (GH) is an important regulator of body composition, reducing body fat by stimulating fat oxidation and enhancing lean body mass by stimulating protein accretion. The emergence of differences in body composition between the sexes during puberty suggests sex steroids modulate the action of GH. Work from our laboratory have investigated the influence of estrogens and androgens on the metabolic actions of GH in human adults. The liver is an important site of physiological interaction as it is a sex steroid responsive organ and a major target of GH action. Estrogen, when administered orally impairs the GH-regulated endocrine and metabolic function of the liver via a first-pass effect. It reduces circulating IGF-I, fat oxidation and protein synthesis, contributing to a loss of lean and a gain of fat mass. These effects occur in normal and in GH-deficient women and are avoided by transdermal administration of physiological doses of estrogen. In contrast, studies in hypopituitary men indicate that testosterone enhances the metabolic effects of GH. Testosterone alone stimulates fat oxidation and protein synthesis, both of which are enhanced by GH. Studies in GH deficiency adults have consistently reported women to be less sensitive to GH than men. In summary, estrogens and androgens exert divergent effects on the action of GH. The results provide an explanation for sexual dimorphism in body composition in adults and the gender-related response to GH replacement in hypopituitary subjects. In the management of hypopituitarism, estrogens should be administered by the parenteral route in women and testosterone be replaced in men to optimize the benefits of GH replacement.

Estimated cost-effectiveness of growth hormone therapy for idiopathic short stature.

OBJECTIVE: To estimate the cost-effectiveness of growth hormone (GH) therapy for idiopathic short stature (ISS). DESIGN: Cost-effectiveness analysis. SETTING: Decision model. PATIENTS: A cohort of 10-year-old prepubertal boys with ISS treated with GH. INTERVENTIONS: Comparison of children treated for 5 years with GH therapy vs children receiving no intervention. MAIN OUTCOME MEASURES: Incremental cost per child, incremental growth per child, and incremental cost per inch of final height gain. RESULTS: The estimated incremental cost-effectiveness ratio of GH therapy for ISS in the base case analysis compared with no therapy was 52,634 dollars per inch (per 2.54 cm), or 99,959 dollars per child, reflecting an incremental growth of 1.9 in (4.8 cm). Alternate treatment strategies such as increased duration of GH treatment and high pubertal dosing of GH did not substantially improve the cost-effectiveness ratio. Probabilistic sensitivity analyses showed that growth variability in response to GH had the greatest impact on the cost-effectiveness of GH therapy. CONCLUSIONS: Targeted treatment of children with ISS with the greatest potential for growth appears critical for maximizing cost-effectiveness of GH treatment. However, the significance of the cost per inch is difficult to judge until the utility gains associated with height gain after GH therapy for ISS can be ascertained.

Welfare effects of the use of recombinant bovine somatotropin in the USA.

The welfare effects of increased milk production associated with the use of recombinant bovine somatotropin (rBST) on dairy operations in the USA were examined for 1996. Results that derived from three different estimates of the milk-production response to rBST were evaluated and compared. One estimate, derived from a survey of dairy producers in Connecticut, led to economic-impact estimates that were not statistically significant. A second, derived from a national survey that concentrated on the health and management of dairy cattle, led to estimates that were unbelievably high. A third, derived from a national survey that concentrated on the economics of dairy producers, provided the most reasonable estimates of economic impacts. Results of economic analysis, using the latter results, indicated that if rBST had not caused milk production to increase, then the market price of milk would have been 2.2 +/- 1.5 cents/kg higher, and the total value of the milk produced would have risen from Dollars 23.0 +/- 0.6 billion to Dollars 24.1 +/- 1.0 billion. A welfare analysis demonstrated that the increased milk production (and the reduced market price) associated with the use of rBST in the USA caused the economic surplus of consumers to rise by Dollars 1.5 +/- 1.0 billion, while the economic surplus of dairy producers fell by Dollars 1.1 +/- Dollars 0.8 billion. Increased milk production associated with rBST yielded a total gain to the US economy of Dollars 440 +/- 280 million. An analysis of annual percent changes in the number of dairy cows per operation, milk production per cow, total milk production, total number of dairy cows, and total number of dairy operations in the USA suggested that the dairy industry's long-term economic growth path was stable from 1989-2001 inclusive, and did not receive a shock resulting from the introduction of rBST.

Treatment of short children born small for gestational age: US perspective, 2005.

Growth hormone (GH) administration to ameliorate growth deficiency of short children born small for gestational age (SGA) is currently approved in the US and the EU. Even though regulatory bodies from each examined similar datasets concerning GH treatment of short SGA children, the specifics of indications for treatment and recommended regimens differed with respect to GH dosage, age at which therapy might be initiated, and the degree of short stature required. US product labeling allows more flexibility but provides less guidance for the practitioner. The EU tends to be more proscriptive, limiting use to shorter children, restricting the dosage, and providing specific guidelines in terms of monitoring during treatment.

An economic evaluation of recombinant bovine somatotropin approval in Japan.

A comprehensive econometric model was developed to evaluate potential impacts of recombinant bovine somatotropin (rbST) approval in Japan. Three novel features of the analyses include 1) investigation of impact of rbST on herd-size structure, 2) determination of economic feasibilities of rbST adoption by herd size, and 3) evaluation of policies to mitigate negative effects of rbST approval. Simulation analysis was conducted over a 10-yr projected period assuming rbST was approved in Japan in 2001. Nine hypothetical scenarios were simulated to examine sensitivity of simulation results. Simulation results indicate that rbST approval would accelerate structural change in Japan's dairy industry toward fewer, larger farms. Negative effects of rbST on farm income are projected to be more severe for smaller farms, because of higher costs, lower profit-earning ability, lower milk yields, and lower adoption rates of rbST. Larger farms benefit from rbST adoption if milk demand is maintained. However, if concerns about rbST induce significant milk demand decreases, even the largest farms' income and cow numbers will decrease. Thus, Japan's dairy industry could be caught in a double downward spiral of declining milk prices and production. Assuming rbST is approved, small farms would benefit by using the technology, but they fare best if rbST is not approved. Two policies could be effective in mitigating possible farm income losses. First, lost farm income can be offset if dairy cooperatives can exercise greater market power to control fluid milk marketings. Second, because generic milk advertising has positive effects on both milk demand and farm income, increasing check-off rates to fund more advertising could ease farm income losses.

High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature.

BACKGROUND: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3-9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost-benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period. AIMS: To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset. METHODS: Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4-8 years for girls or 4-10 years for boys, GH concentration >10 micro g/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment). RESULTS: In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls. CONCLUSIONS: High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS.

[Once growth hormone, always growth hormone? Transition from growth hormone therapy in childhood to adulthood]. / Eenmaal groeihormoon, altijd groeihormoon? De transitie van groeihormoonbehandeling van kind naar volwassene.

The continuation of growth hormone treatment can be indicated in young adults who have been treated with growth hormone during childhood. However, in a large part of this population the diagnosis cannot be confirmed in adulthood. Therefore a retest procedure has to be performed once the final height has been attained. This procedure is only unnecessary in patients with deficiencies of two or more other pituitary hormone axes. The retest procedure can be performed one to three months after the growth hormone treatment has been discontinued, by means of an insulin tolerance test or, in the case of contraindications, by means of a combined growth hormone-releasing hormone(GHRH)-arginine test. If the growth hormone deficiency diagnosis is re-established, growth hormone treatment can be restarted. Patients are only eligible for a reimbursement of the growth hormone treatment costs from their health insurer, if the treatment indication is validated by the Dutch National Registry of Growth Hormone Treatment in Adults and the treatment results are included in a database. With this database insights into the long-term efficacy and safety of growth hormone treatment can be gained.