Running title: Growth hormone coverage for idiopathic short stature

Transcription

1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof AACE. Original Article EP CHALLENGES OF SECURING GROWTH HORMONE COVERAGE FOR IDIOPATHIC SHORT STATURE: REVIEW OF THE 7 YEAR EXPERIENCE AT ONE INSTITUTION Marie Christianne Sandhya Ravi Chandar, MBBS 1 ; Paul B Kaplowitz MD, PhD 2 ; Priya Vaidyanathan MD 3 1 Metrohealth Medical Center, Cleveland Ohio 44109; 2 Children s National Health System, 111 Michigan Ave NW, Washington, DC 20010; 3 Division of Endocrinology, Children's National Health System, 111 Michigan Ave NW, Washington, DC Corresponding author: Paul Kaplowitz, MD Children s National Health System, 111 Michigan Ave NW, Washington, DC Phone: : Fax ; pkaplowi@childrensnational.org for Marie Ravi Chandar: mravichandar@metrohealth.org for Dr.Vaidyanathan: pvaidyan@childrensnational.org There were no funding sources for this study Running title: Growth hormone coverage for idiopathic short stature Keywords: idiopathic short stature, growth hormone therapy, predicted adult height Take away points 1. Many short children who pass GH testing meet the FDA criteria for idiopathic short stature and are unlikely to reach a normal adult height without treatment. 2. Managed care companies in the DC area approved requests for GH from our department only 36% of the time, including appealed cases. There was no significant difference between approved and rejected cases. 3. There are opportunities for medical directors of managed care companies and pediatric endocrinologists to develop guidelines together which would allow improved access to GH for very short ISS children, without substantially increasing treatment cost.

2 Abstract: Background: Despite FDA approval of growth hormone(gh) for idiopathic short stature(iss), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial. Methods: We reviewed charts of patients who underwent GH stimulation testing from 07/01/09 to 04/30/17 to identify ISS patients (height <-2.25SD, subnormal predicted adult height(pah) and peak GH >10ng/ml) Results: 87 patients met ISS criteria, of whom 47(29M/18F) had GH request submitted to insurance. Mean age, height and growth velocity were 8.6±2.7years,-2.83±0.4SD and 4.4±1.7cm/yr respectively. Mean PAH based on bone age was ±0.9SD, equaling 62 for males and 58 for females. Most had private managed care insurance (74%). 17/47(36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after one year. Conclusion: At our institution, GH coverage requests for ISS included very short children mostly ages 6-11, with heights well below SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve costeffective coverage to deserving short children who meet FDA guidelines for ISS treatment. Abbreviations: ISS = idiopathic short stature; GH = growth hormone; PAH = predicted adult height; FDA = Food and Drug Administration ; IGF-1 = insulin-like growth factor 1.

3 Introduction: In 2003, the FDA approved the use of growth hormone (GH) for children with idiopathic short stature (ISS). This was based on several studies documenting an increase in adult height relative to an untreated control group (1, 2) or predicted height at the start of treatment (3, 4). To meet this criterion, height needed to be below the 1.2%ile (<-2.25 SD) without any evidence for underlying growth-limiting disease or GH deficiency, and the children should have a growth rate that is unlikely to attain an adult height within the normal range. This decision was quite controversial, with some believing that treatment of short but otherwise normal children should not be encouraged (5), especially since it has been difficult to demonstrate a clear psychological benefit to the child (6,7). Some groups have endorsed this therapy in selected patients, with a 2008 consensus statement concluding the shorter the child, the more consideration should be given to GH (8). In the 15 years since this decision, the use of GH for short stature not due to GH deficiency has expanded considerably, and there are now at least 7 companies which market GH for pediatric indications. However, insurers in different geographic areas of the US vary greatly in their willingness to approve such requests. Many managed care companies have taken the view that prescribing GH for a short child, without GH deficiency or one of the other approved indications for GH therapy, does not meet their definition of medically necessary. At our institution, providers have long noted difficulties in getting insurance approval for GH therapy, for children who meet the criterion for ISS. It appears to be much easier to get approval for a mildly short child with a peak GH on provocative testing slightly below the cut-off of 10ng/ml, than to get approval for an extremely short child with a peak GH of >10ng/ml. We therefore undertook a review of our experience with obtaining approval of GH for ISS, over an 8 year period, to see if we could identify any factors which made it more likely for such requests to be approved. Methods: In order to capture all patients with a diagnosis of ISS for whom a request for GH was submitted, we obtained a list through billing records of all patients who underwent GH stimulation testing between 7/1/09 and 4/30/17. The method for testing was administration of glucagon followed by arginine with samples drawn every 30 minutes for 3 hours. We reviewed the charts of all patients whose peak GH during testing was >10 ng/ml. Patients who met the criteria of ISS were those who had a height SD of < SD at the time of GH testing and a predicted adult height (PAH) based on bone age and the Bayley-

4 Pinneau charts of < -2 SD. For the few patients whose bone age was below 6 years and for whom we were unable to calculate PAH, a height of <-2.25 SD was considered sufficient. Pre-treatment growth velocity was not always available and was not used to define ISS. Information extracted from the chart review included age and height SD score at the time of the GH stimulation testing, growth rate if more than one pre-treatment height was available, heights of parents, IGF-1 levels, bone age, medications which might impact on growth, the type of insurance (public vs private), and the results of submission to insurance for coverage of GH. While we do not have a precise figure, the majority of the insurance providers, both public and private, were managed care companies. For those who were started on treatment, we looked at the height SD change during the first year of therapy. Mid-parental target heights were converted to SD scores based on sex, and IGF-1 levels were also converted to SD scores based on age and sex. Pubertal staging was taken into account but very few patients had started puberty. The study was approved by the institutional review board. Results: Of the 87 patients felt to meet the criteria of ISS, 47 had documentation of a request submitted to the insurance company to cover GH therapy, and for another 40, no such request was submitted. Also identified were 24 patients who passed GH testing, with significantly delayed bone ages, and were felt to have constitutional growth delay; several of those received treatment with testosterone or oxandrolone. Of the 47 patients for whom approval for GH therapy was requested, only 7 patients (15%) received approval after the initial submission. The letters from the insurance companies in most cases gave the reason for rejection as Does not meet criteria, as ISS is not approved for GH therapy, or ISS is not a medical necessity or a disabling medical condition requiring treatment or GH therapy is not done for cosmetic indications. Thirty of the 40 rejections were appealed and in the appeal letter, the low PAH, which was not included in the initial Statement of Medical Necessity form, was emphasized; in this process an additional 10 patients were approved. Of the 30 patients for whom GH therapy was not approved, 12 families paid for GH out of pocket, 10 received GH through drug company patient access programs, and 8 were not treated.

5 Characteristics of patients for whom there was an attempt made to secure GH coverage are shown in Table 1 and compared with the group of 40 patients who passed GH testing and for whom no request for GH coverage was submitted. The mean age of the group of 47 patients for whom an application for GH was submitted to insurance was 8.6 years, and 35 of the 47 were between the ages of 6 and 11. Mean height was ± 0.39 SD. Mean growth velocity was 4.43 ± 1.73 cm/yr, which is low-normal for 6-11 year olds. They were seen on the average 2.3 times before GH stimulation testing was performed. Mean IGF-1 SD was below average for age but was <2 SD in only 3 patients. Bone age was on average 1 year delayed. Mean target height was somewhat low at SD (equal to 66.5 for males and 62 for females) but mean predicted adult height (PAH) SD score based on current height and bone age was only ± 0.89 SD, which is equal to 62 for males and 58 for females. Seven of the 47 had a diagnosis of ADHD and were taking stimulant medications., while 2 were taking inhaled steroids for asthma. The 40 patients for whom GH was not requested were on the average significantly older, and had a mean paternal height, mid-parental heights and PAH which were not as short as those for whom GH was requested. None of the other parameters we examined were different for the two groups. Four were taking stimulant medication for ADHD. Only 8 of 40 (20%) returned for another visit after their GH testing. We then examined whether there were any significant differences between the patients who were either initially or after appeal approved for GH vs those who were rejected. As shown in Table 2, the two groups were similar in all the characteristics examined and none of the differences were statistically significant. We did however find that the for the subset of 10 patients for whom GH was approved after appeal, the mean height velocity of 3.62 ± 1.03 cm/yr was significantly lower than for the group of 25 for whom we had a pretreatment growth velocity, and who were subsequently rejected upon appeal (4.66 ± 2.07 cm/yr; p=0.05). Of the 39 patients who eventually received GH, we had follow-up measurements approximately 1 year into therapy on 21, which showed a mean increase in height SD of 0.6, with a wide range of 0.2 to 1.1. Discussion: In this review of the experience at a large urban children s hospital, we found that requests for coverage of growth hormone therapy using the diagnosis of ISS were generally limited to patients who met the

6 strict criteria that the FDA set forth when they approved GH for this indication in The mean height SD of was well below the FDA cutoff for ISS of SD. The mean PAH SD was -2.5, equivalent to 62 in boys and 58 in girls. It was also noted that prior to GH testing, most patients had had at least 2 visits (mean 2.3) so that baseline growth rate could be assessed, prior to deciding whether to undertake GH testing. The mean growth rate was 4.43 cm/yr, which for an 8.5 year old (the average age of our group) is equal to the 10 th %ile on standard height velocity charts. As expected for patients who passed GH stimulation testing, IGF-1 levels were not low in most cases, with a mean IGF-1 SD of SD. Many but not all patients had at least one short parent, and the mid-parental height SD was somewhat below average, indicating some genetic contribution to their short stature. Bone age was on the average 1.0 years delayed but not as delayed as in most patients with constitutional growth delay, in whom bone age is delayed by >2 SD. For the children of average age in this study (8 years), the SD for bone age according to the Gruelich and Pyle atlas is 10.8 months in boys and 8.8 months in girls, so a bone age delay of > 2 SD would be in the range of months. Nine of 47 were taking medications (mainly stimulants for ADHD) which may have impacted their growth somewhat, but based on the rejection letters this did not appear to factor into the decision to approve or reject growth hormone therapy. We compared the group of 47 patients for whom GH coverage was requested with the group of 40 patients felt to have ISS for whom GH was not requested. The latter group was significantly older, growing slightly better, and had a mean PAH SD which was significantly higher compared to the group for whom GH was requested. From the chart review there were a variety of reasons as to why GH was not requested. In some cases the parents were reassured that there was no hormonal deficiency and did not wish to pursue GH therapy (likely having been made aware of the difficulties in getting it approved). In other cases the provider felt that the growth prognosis was satisfactory or that both the height SD and adult height criteria for ISS were not fully met, and recommended further monitoring of growth before deciding if GH therapy should be pursued. For some patients, mention was made of pursuing GH therapy but there were no follow-up visits. In fact, for only 8 of the 40 patients (20%) in this group were there any further visits for monitoring of growth. It appears that for most families for whom GH therapy was not requested after GH stimulation testing, further visits to assure that growth was not falling further below the curve were not a high priority.

7 We next compared the 17 patients, for whom GH coverage by either private or public insurance was approved, with the 30 patients for whom it was denied, in many cases, even after appeal. The 2 groups were strikingly similar in all characteristics we examined. When we looked at the 10 cases where GH was approved after appeal, their mean growth rate was somewhat lower (3.62 cm/yr) than the group for whom GH was rejected (4.67 cm/yr; p=0.05), suggesting that low growth rate may have been one factor which made successful appeal of a denial for GH coverage more likely. The proportion of patients in the denied group who had private insurance vs public, was higher than in the approved group (80% vs 65%) but the difference was not significant. Most of both groups were insured by managed care companies. We did confirm that patients got at least short term benefit from therapy, with a mean increase in height SD of 0.6 SD in the first year. This is very similar to what was reported using the Genentech National Cooperative Growth Study database, where the mean increase in height SD during the 1 st year of treatment of a cohort with a mean age of 10.5 years was (9). The issue of GH treatment for ISS remains controversial. The most recent Pediatric Endocrine Society guidelines (10) include the following statement: In the USA, for children who meet FDA criteria, we suggest a shared decision-making approach to pursuing GH treatment for a child with ISS. The decision can be made on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits. We recommend against the routine use of GH in every child with height SDS (Ht SDS) The prediction of an individual's spontaneous adult height (AH) involves the utilization of information about parents' heights, bone age, and growth in untreated cohorts to determine the assumed height target. Patients with ISS and their families should be counseled about heterogeneity in response to GH; i.e., while on average there will be an approximately 5-cm (2-inch) increase in AH with approximately 5 years of GH treatment, individual responses are highly variable, including no measurable increase in height SDS in some patients. We agree that the decision to recommend a trial of GH for ISS should be weighed carefully and that families should not receive overly optimistic projections as to the long-term benefit. The guidelines did recommend starting on somewhat lower GH dosing than the 0.3 mg/kg/week dosing than many providers use, stating Because there is overlap in response between dosing groups, we suggest initiating GH at a dose of 0.24 mg/kg/week, with some patients requiring up to 0.47 mg/kg/week.

8 We conclude that, as at least concerns the insurance companies in the Washington DC area, for children who do not test GH-deficient, the decision as to who gets insurance coverage for GH and who does not is unrelated to either the degree of shortness (height SD) or our prediction based on bone age as to how tall the child will be as an adult. There are studies which show that the response to GH in children with ISS is nearly as good as in children with GH deficiency for whom GH therapy is readily approved (11), while other studies suggest that children with GH deficiency are more responsive to GH than children with ISS (12). Thus the strict use of the cut-off of 10 ng/ml for deciding which short children would benefit from GH therapy denies treatment to many children who would benefit. In a paper based on a round-table discussion involving pediatric endocrinologists and managed care professionals, it was pointed out that managed care organizations recognize that ISS may be a valid medical condition. However they try to balance the needs of the patient with the economic realities of the healthcare system. Because it may be challenging to directly measure the long-term benefits of GH therapy, payers may focus on short-term costs. (13) These costs are high because unlike many expensive medications, GH usage can extend over a period of many years. Thus, if we wish managed care companies to revise their guidelines for use of GH in ISS, we may need to balance wider access with somewhat stricter approval criteria. We therefore propose the following 6 items which would significantly decrease the overall cost of GH therapy while allowing this treatment for deserving very short children. 1: We propose a height cut-off of -2.5 SD (0.6%ile) instead of SD (1.2%ile), which would decrease the number of children eligible for GH therapy under the ISS indication substantially 2: We also propose a growth rate of <4.5cm/year or <25 th %ile for age, though children with extreme short stature (e.g. height -3.0 SD) deserve treatment even with a normal growth rate. 3: PAH of no more than 64 in boys and 60 in girls could be required for approval. These heights represent the 3 rd %ile for adult men and women 4. Growth hormone stimulation testing should not be needed if the above criteria are met in short children with normal IGF-1 levels which would result in further cost savings. 5. A starting dose of 0.24 mg/kg/week as proposed in the recent published guidelines, which is 20% less than the standard starting dose of 0.3 mg/kg/week. 6. Stopping treatment once the child has reached the normal range in height for those children who are growing well after onset of puberty, as suggested in a recent commentary (14). While there are no controlled studies comparing growth in ISS children in puberty with and without GH, anecdotal

9 experience suggests that the endogenous increase in GH secretion during puberty is sufficient to sustain rapid growth once GH is discontinued. Since many providers adjust the dose of GH based on weight rather than on growth rate, reducing the use of GH in pubertal children with ISS would result in significant cost savings. While some companies have modified their treatment guidelines to make GH accessible for very short children with normal GH testing, in the DC area at least, a peak GH of <10 ng/dl is still the primary criteria used for approval. Further discussions on this subject with medical directors of large insurance plans would be welcome, though with the large number of managed care companies in the US, this could be a very protracted process. A more successful strategy may be to convene a consensus conference of leading pediatric endocrinologists and representatives of the largest managed care companies to develop a proposal along the lines suggested above that could be adopted more broadly. References: 1. Leschek EW, Rose SR, Yanovski JA et al. Effect of growth hormone treatment on adult stature in peripubertal children with idiopathic short stature: A randomized, double blind, placebocontrolled trial. J Clin Endocrinol Metab 2004;89: Albertsson-Wikland K, Aronson S, Gustafsson J, et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metab 2008;93: Hintz RL, Attie KM, Baptista J, Roche A and the Genentech Collaborative Group. Effect of growth hormone on adult height of children with idiopathic short stature. N Engl J Med 1999;340: Wit JM, Rekers-Mombarg LTM, Cutler GB et al. Growth hormone treatment to final height in children with idiopathic short stature: Evidence for a dose effect. J Pediatr 2005;146:45-53.

10 5. Rosenbloom RL. Idiopathic Short Stature: Conundrums of Definition and Treatment. Int J Pediatr Endocrinol 2009;2009: Ross JL, Sandberg DE, Rose SR et al. Psychological adaptation in children with idiopathic short stature treated with growth hormone. J Clin Endocrinol Metab 2004;89: Sandberg DE and Gardner M. Short stature: Is it a psychosocial problem and does changing height matter? Pediatr Clin North Am. 2015;62: Cohen P, Rogol AD, Deal CL et al. Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008;93: Kemp SF, Kuntze J, Attie K et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab 2005;90: Grimberg A, DiVall S.A, Polychronakos C, et al. Guidelines for Growth Hormone and Insulin- Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr 2016;86: Frindik JP, Kemp SF, Hunold JJ. Near adult heights after growth hormone treatment in patients with idiopathic start stature or idiopathic growth hormone deficiency. J Pediatr Endocrinol Metab 2003;16: Hughes IP, Choong HM, Cutfield AG et al. Growth hormone regimens in Australia: Analysis of the first 3 year of treatment for idiopathic growth hormone deficiency and idiopathic short stature. Clin Endocrinol 2012;77:62-71.

11 13. Navarro R, Dunn JD, Lee PA, Owens GM, Rapoport R. Translating clinical guidelines into clinical practice: The effective and appropriate use of human growth hormone. Am J Manag Care 2013;19 (14 suppl): S Allen DB. Growth promotion ethics and the challenge to resist cosmetic endocrinology. Horm Res Paediatr 2017;87:

12 Table 1: Characteristics of children with ISS based on whether a request for GH was submitted to insurance Group submitted to Group not submitted to insurance (n=40) insurance (n=47) Age (years) at time 8.60 ± ± 3.1 (p=0.011) of GH stimulation testing Sex 29 M / 18 F 29 M / 11 F Height SD ± ± 0.57 Pretreatment height 4.43 ± ± 2.06 velocity (cm/year) Number of visits 2.28 ± 1.66 * prior to GH testing Bone age 7.63 ± 2.35 * IGF-1 SD ± 1.04 * Maternal height 61.6 ± ± 2.6 (inches) Paternal height 66.7 ± ± 2.4 ( p=0.006) (inches) Mid parental height ± ± 0.74 (p=0.034) SD Predicted adult height SD ± ± 0.87 (p=0.019) *Charts reviewed in less detail and some items not captured

13 Table 2: Comparison of patients with ISS for whom GH was approved vs not approved GH approved (n=17) GH not approved (n=30) Age (years) at time of 8.61 ± ± 2.81 GH stimulation testing Sex 11 M/ 6 F 18 M / 12 F Height SD ± ±0.36 Pretreatment height 4.07 ± ± 2.02 velocity cm/year Number of visits prior 2.00 ± ± 1.81 to GH testing IGF-1 SD ± ± 0.99 Maternal height 61.7 ± ± 2.2 (inches) Paternal height 66.8 ± ± 4.5 (inches) Mid parental height ± ± 0.93 SD Predicted adult ± ± 0.79 height SD Insurance 6 public/ 11 private 6 public/ 24 private None of the differences were statistically significant