Examining Growth Outcomes Studies: A Perspective on the Clinical Benefit, Risk, and Cost of rhGH Therapy

Growth hormone (GH) therapy increases final adult height when used to treat a number of FDA-approved indications, including idiopathic growth hormone deficiency (IGHD), Turner syndrome, idiopathic short stature (ISS), and infants born small for gestational age (SGA). However, in addition to the expected height gains with GH therapy, it is essential that clinicians, patients, and their parents understand the potential risks associated with treatment. Economic considerations are also important in routine clinical practice, and recent research has examined the cost-effectiveness of GH therapy using outcome measures such as the cost per centimeter of height gained. This article provides an overview of the peer-reviewed literature on GH therapy, with an emphasis on studies that have enrolled large numbers of patients and results from large postmarketing surveillance databases such as the Kabi International Growth Study (KIGS) and the National Cooperative Growth Study (NCGS). Although many studies have reported results using standard deviation (SD) units, for the purposes of this review these scores were converted to centimeters of height gained using SD score growth charts developed by the Centers for Disease Control and Prevention (CDC). Expressing height gain in centimeters may be more intuitive for clinicians and families to interpret. Using these charts, a difference of 1 SD unit is approximately 7.25 centimeters for boys, and slightly less for girls.¹ Converting scores to centimeters also allowed us to calculate the cost per centimeter of height gained with GH therapy. Finally, it should be noted that in most studies of GH therapy in pediatric patients, patients are not treated until they attain final adult height because some continued growth occurs over several years into young adulthood after treatment is discontinued. Studies generally report the near final adult height (NFAH), which is usually defined as the height when the patient reaches a bone age of 14 years for females or 16 years for males, with an annualized growth velocity of less than 2 centimeters per year.² NFAH is generally very close to final adult height, usually within 0.3 SD units.

Idiopathic Growth Hormone Deficiency

In patients with IGHD, a review of studies with a combined patient population of 1,400 patients found that the NFAH was 1.3 SD units below normal.^3-6 The mean dose of GH was 0.2 mg/kg/week for a period of 7 years. A very similar outcome was noted in an examination of growth outcomes using the KIGS database, with 1,221 patients with IGHD.⁷ The mean height at the beginning of treatment was 3.1 SD units below normal, which improved to 1.4 SD units below normal at NFAH. This height gain of 1.7 SD units is equivalent to 12.3 centimeters for males and 10.2 centimeters for females. A height gain to within 2 SD units of normal (the lower limit of normal height) was achieved by 73% of patients. The median final adult height was approximately equal to the median midparental height, implying that 100% of the patients treated attained their target heights.

Multiple Pituitary Hormone Deficiency

Data from the KIGS database were used to examine the effect of GH therapy for 686 patients with multiple pituitary hormone deficiency (MPHD).⁷The median GH dose for these patients was 0.18 mg/kg/week for 9 years. The mean height increased from a baseline of 3.7 SD units below normal to an NFAH of 1.2 SD units below normal, an improvement that was similar to that observed for patients with IGHD. This height gain of 2.5 SD units corresponds to 18.1 centimeters for males and 15 centimeters for females. Improvement to a height within 2 SD units below normal was attained by 75% of patients. Again, the median final adult height was approximately equal to the median midparental height, implying that all patients achieved their target heights.

Turner Syndrome

In patients with Turner syndrome, reports of height gain include a 7.2 centimeter increase in a randomized clinical trial conducted in Canada,⁸ a gain of 8.4 centimeters in a study conducted in France,⁹ and 11.9 to 16.9 centimeters gained in a study conducted in the Netherlands.¹⁰ The largest increases in growth were attained in patients who received the highest GH doses. Patients with Turner syndrome often have estrogen deficiencies or ovarian failure and are treated with estrogen, and low estrogen doses have also been shown to improve height gain.¹¹ Patients in the Canadian and Dutch studies began treatment at or before the typical age of onset of puberty (at ages up to 13), whereas patients in the French study started somewhat later, at a mean age of approximately 15 years. In addition, data were available from 1,146 patients with Turner syndrome in the KIGS database.¹² Height increased from a mean height of 3.1 SD units below normal to 2.3 SD units below normal, for a height gain of approximately 9 centimeters. A final height of 2 SD units below normal or better was attained by 40% of patients. On average, patients received a GH dose of 0.28 mg/kg/week for a period of 6.7 years, a dose that may be somewhat lower than most clinicians use for Turner syndrome in routine clinical practice.

Idiopathic Short Stature

Evidence from randomized clinical trials suggests that patients with ISS experience a mean height gain of approximately 7 centimeters using a GH dose of 0.35 mg/kg/week.¹³In the KIGS database, data were available for 327 patients with ISS.¹⁴ The mean height at the beginning of treatment was 3.1 SD units below normal, which improved to a final height of 1.7 SD units below normal after treatment with growth hormone at a dose of 0.19 mg/kg/week for a mean of 6.6 years. This height gain of 1.4 SD units translates to approximately 10.15 centimeters. An NFAH within 2 SD units below normal height was achieved by 60% of patients. The median NFAH was nearly equal to the median parental height, suggesting that many children with ISS have relatively short parents.

Small for Gestational Age, Silver-Russell Syndrome

Data from the KIGS database are available for fewer patients with SGA or Silver-Russell syndrome (SRS). For SGA, there were 65 patients enrolled in the KIGS database.¹⁵ The mean height increased from 3.6 SD units below normal at baseline to 2.1 SD units below normal by the end of treatment, which is close to the lower boundary of the normal range. The mean height gain of 1.3 SD units corresponds to 9.4 centimeters. The mean GH dose was 0.24 mg/kg/week for 7.7 years, which is substantially lower than the currently approved dose of 0.48 mg/kg/week. One-half of patients attained a height within 2 SD units below the normal height. The final adult height was 1 SD unit below the median parental height.

For SRS, 39 patients were available in the KIGS database.¹⁵ These patients had a mean pretreatment height of 4 SD units below normal, which improved by the end of treatment to a mean height of 2.9 SD units below normal. The mean height gain was 1.3 SD units (9.4 centimeters), with a mean GH dose of 0.26 mg/kg/week for a mean treatment period of 7.9 years. Only 25% of these patients attained a normal NFAH (within 2 SD units below the normal height). The final adult height was 2 SD units below the median parental height.

Cost of Treatment

Determining the exact financial cost of the height gained with GH therapy is impossible due to a number of factors, including limited information about individual weight changes across a period of 6 to 8 years, variable purchase prices for different GH products, varying amounts used by different patients, and the fact that patients frequently switch from one GH product to another. Even determining the per-milligram cost of a single GH formulation is complicated by the variety of different costs (eg, average wholesale price vs. wholesale acquisition cost), discounts and rebates, and different prices negotiated by insurers, pharmacy benefit managers, and government programs such as Medicaid.

The average monthly cost of GH therapy was estimated using price information from a pharmaceutical supplier in Texas from 2003 to 2010 (unpublished data). The average per-month cost of GH was estimated at $2,310 for the years 2003 to 2005 (based on more than 9,000 shipments), which increased to $3,261 in 2009 (based on 2,000 shipments) and $3,365 in 2010 (based on 2,000 shipments). Children who receive GH are often treated for 6 to 9 years. Thus, for a hypothetical patient who is treated for 100 months (approximately 8 years) at a monthly cost of $3,000, the total cost of therapy would be $300,000. If the patient gained 10 centimeters in height, the cost per centimeter would equal $30,000. Considering mean height gain and the estimated cost per centimeter of height assuming a treatment cost of $3,000 per month, the per-centimeter cost of treatment for the aforementioned indications is between $20,000 and $30,000 (Table 1). These estimates include only the cost of GH itself. Other costs in the evaluation and treatment of children with short stature include karyotyping, assessment of insulin-like growth factor (IGF)-1 and IGF-3 levels, thyroid function, sedimentation rate, GH testing (which may cost $5,000 to $6,000), and costs for 4 annual visits over a period of 6 to 8 years (which may total approximately $4,200). Annual assessment of bone age and IGF-1 may cost approximately $1,400 per year. Furthermore, there are costs associated with the 24 days of absence from school or work over the course of treatment and a total of 2,555 injections.

Table 1. Cost of Growth Hormone

Key: IGHD — idiopathic growth hormone deficiency; ISS — idiopathic short stature; MPHD — multiple pituitary hormone deficiency; SGA — small for gestational age; SRS — Silver-Russell syndrome
Source: Paul Thornton, MD

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Adverse Events

Some of the most common adverse events associated with GH therapy include slipped capital femoral epiphysis (SCFE), scoliosis, type 2 diabetes mellitus, and raised intracranial pressure. According to the KIGS database, adverse event rates vary somewhat among the different indications for growth hormone treatment (Table 2).¹⁶ For example, the incidence of SCFE is higher among patients with Turner syndrome compared to those with IGHD, ISS, or Prader-Willi syndrome, whereas scoliosis is much more common among patients with Prader-Willi syndrome and, to a lesser extent, in patients with Turner syndrome. Type 2 diabetes is also more common in patients with Prader-Willi syndrome, which may reflect the relatively high incidence of obesity in these patients. Raised intracranial pressure, or pseudotumor cerebri, typically occurs soon after treatment is initiated.

Table 2. Risk of Side Effects

Expressed at adverse event/treatment-years
Key: IGHD — idiopathic growth hormone deficiency; ISS — idiopathic short stature; PWS — Prader-Willi syndrome; T2DM — type 2 diabetes mellitus; RICP — raised intracranial pressure; SCFE — slipped capital femoral epiphysis
Source: Wilton P, et al. In: Ranke MB, Price DA, Reiter EO, eds. Growth Hormone Therapy in Pediatrics: 20 Years of KIGS. Basel, Karger; 2007:432-441.

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Summary and Conclusions

NFAH data for patients treated with GH therapy are available for only a subset of all patients who have been treated. Most of those who receive GH in routine clinical practice are never enrolled in a clinical trial or a patient registry. Long-term follow-up studies have generally not evaluated patients until final adult height. Despite these limitations, the available data demonstrate that there is reasonably good concurrence between peer-reviewed clinical trials and phase 4 postmarketing observational studies for the typical height improvement obtained with GH therapy in a variety of clinical settings. Estimating the cost of treatment is important, but is complicated by variable drug acquisition costs, GH doses, duration of treatment, and other factors. However, it is also difficult to determine the economic and psychological costs of not treating children with short stature. Despite an increase in the number of pharmaceutical companies that manufacture GH over the last several years, the cost of GH therapy has increased, and not decreased, over time.

References

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