Introduction

There are currently nine recombinant human growth hormone (rhGH) products available in the USA for ten different indications [1]. Most of these rhGH products are approved for one or more indications. Growth hormone deficiency (GHD), idiopathic short stature (ISS), and Turner syndrome (TS) are some of the indications for which an rhGH is prescribed. Patients with GHD or ISS make up the majority of the pediatric population receiving growth hormone treatment [1]. GHD affects ~1 in 3,500 children [2]. In 2003, the Food and Drug Administration approved rhGH for children with ISS whose height is more than 2.25 standard deviations (SD) below the mean (or below the 1st percentile). Since the specific etiology for ISS in children is sometimes difficult to identify, children are often diagnosed with ISS and receive growth hormone (GH) therapy [3, 4]. TS occurs ~1 in 2,000–2,300 live female births [5].

Omnitrope® (Sandoz) is one of the rhGH products available in the USA. It was developed as a medicinal product similar to the reference rhGH product, Genotropin® (Pfizer Inc.). Long-term studies comparing Omnitrope and Genotropin have shown similar efficacy and safety [6–9]. Physicians are often confronted with the need to change the rhGH used by their patients due to health plan and/or patients’ insurance demands. Thus, there is a need for data demonstrating what impact switching rhGHs has on patients’ auxological measurements. During 2009, Kaiser Permanente Southern California (KPSC) had a formulary change which transitioned patients on other rhGHs to Omnitrope, thus providing a unique opportunity to evaluate the effects of switching preparations.

The primary objective of this study was to evaluate the effectiveness of Omnitrope on children with GHD, who switched from a non-Omnitrope rhGH preparation during routine clinical care. Secondary objectives were to evaluate the effectiveness of Omnitrope on children with an alternative diagnosis such as ISS or TS. This study considered quantitative outcomes evaluating change in auxological parameters such as height, height standard deviation score (HSDS), height velocity (HV), and height velocity standard deviation score (HVSDS) from time of their switch to Omnitrope until 15 months post-switch.

Methods

Setting

KPSC is a non-profit, group-model, health maintenance organization (health plan) providing integrated healthcare services to more than 3.6 million active members in Southern California, USA. The health plan covers the seven most populous counties in Southern California, from Los Angeles south to San Diego and east to the inland counties of Riverside and San Bernardino. KPSC membership closely mirrors the Southern California population, is racially diverse and includes the entire socioeconomic spectrum [10, 11]. Patient information on demographics and healthcare encounters (diagnoses, procedures, laboratory results, and prescriptions) are captured in the KPSC electronic medical record (eMR) system. KPSC members receive the majority of their healthcare and prescriptions at Kaiser Permanente facilities, which provides an ideal environment to conduct research studies.

Study Design and Patients

This retrospective cohort design study was conducted for the KPSC region only and was approved by the KPSC Institutional Review Board. Patients included in the study had GHD, ISS, or TS, and were switched to Omnitrope from another non-Omnitrope rhGH therapy between January 1, 2006 and July 31, 2011. We identified GHD, ISS, or TS by International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM) of 253.xx (GHD), 783.xx (ISS), and 758.6 (TS). Each chart was then further reviewed to evaluate the diagnosis and code. Index date was defined as the date the patient switched from non-Omnitrope rhGH to Omnitrope. Pre-switch was defined as 15 months prior index date and post-switch as 15 months duration after the index date. Additional inclusion criteria were continuous membership and drug benefit eligibility in KPSC for 15 months pre-switch and 15 months post-switch; age <18 years on index date; and in receipt of a non-Omnitrope rhGH therapy for 15 months pre-switch. The 15-month pre-switch criteria were incorporated to limit potential bias associated with “catch-up growth” that is observed during initial GH therapy. The study observation period ended on October 31, 2012 so that each patient had a 15-month post-switch follow-up period. Patients had to have at least three documented visits that were 3 months apart in the 15 months pre-switch and at least three visits that were 3 months apart in the 15 months post-switch. The visits had to span more than 9 months before and after the index date. Once the initial cohorts were assembled, patients were further categorized according to their pubertal stage via Tanner staging [12, 13]. Patients with a Tanner stage of <2 were categorized as pre-pubertal and patients with Tanner stage of ≥2 categorized as pubertal.

Efficacy Assessments

The primary study outcomes were auxological changes in height, HSDS, HV, and HVSDS from the index date to 15 months post-switch. The height measurement closest to the index date was the baseline value. All patients had their baseline height value within 7 days prior to switching to Omnitrope. HV (cm/year) was calculated as the difference between two height measurements divided by the time interval between these two measurements multiplied by 365.25. Standardization of height used US Centers for Disease Control and Prevention reference ranges of body height and the mean and SD ranges of normally growing children [14] taken from tables provided by Tanner et al. [15]. Standardization of HV was based on the table provided by Tanner et al. [15]. We required three visits pre- and post-switch; when visits did not fall into the exact time position, we interpolated the data; we used the closest before and after height measurements to the time position of need and calculated the height point.

Statistical Analysis

Descriptive statistical analysis was performed using SAS Version 9.2 (SAS Institute Inc., Cary, NC, USA). Continuous parameters were summarized using descriptive statistics including mean and SD. Categorical parameters were summarized using frequencies and percentages. We conducted a quasi-experimental analysis in which the subjects were evaluated pre- and post-switch to Omnitrope therapy.

Results

Patient Characteristics

A total of 103 patients were included in the study: 57 patients with GHD, 26 with ISS, and 20 with TS. Patient baseline clinical characteristics are summarized in Table 1. There were slightly more pre-pubertal patients than pubertal patients among the GHD and TS patients, whereas the opposite occurred among the ISS patients. Similarly, the pre-pubertal patients were younger among the GHD and TS groups than in the ISS children. The youngest patient was 4-year old with TS. The mean total dose of rhGH given to the patients was similar among the three groups of patients during the pre-pubertal and pubertal stages. The mean duration patients were on a non-Omnitrope rhGH therapy was 4.6 years (SD ±1.24 years, minimum 1.52 years, maximum 5.84 years).

Table 1 Patient baseline characteristics
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Height

The mean overall height at index date was 137.76 ± 18.72 cm for all patients, and the mean height at 15 months post-switch for all the patients was 144.28 ± 18.52 cm, showing an increase of 6.52 cm (Table 2). Within each category, the subjects’ mean height at the index date was 137.37 ± 21.26 cm, 145.11 ± 14.75 cm, and 129.31 ± 10.68 cm for the patients diagnosed with GHD, ISS, and TS, respectively. After 15 months of Omnitrope treatment, those with GHD grew (on average) by 6.30 cm, those with ISS grew (on average) by 6.58 cm, and those with TS grew (on average) by 6.52 cm (Table 3). Height profiles of each participant during the 15-month pre- and post-switch period relative to the time of their index date are shown in Figs. 1 (all patients) and 2 (by indication).

Table 2 Summary of height, HSDS, HV, and HVSDS 15 months pre- and post-switch (all patients)
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Table 3 Summary for height, HSDS, HV, and HVSDS 15 months pre- and post-switch (by indication)
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Fig. 1
figure 1

Individual height profiles versus time from the switch

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Fig. 2
figure 2

Individual height profiles versus time from the switch by indication. GHD Growth hormone deficiency, ISS idiopathic short stature, TS Turner syndrome

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Height SDS

The mean HSDS for all subjects at index date was −1.49 ± 1.01; HSDS increased by an average of 0.04 over the 15-month post-switch period (Table 2). Within each category, the subjects’ mean HSDS at the index date was −1.23 ± 1.06, −1.70 ± 0.80, and −1.97 ± 0.90 for the patients diagnosed with GHD, ISS, and TS, respectively. Those with GHD improved, on average, by 0.07; those with ISS improved, on average, by 0.13; patients with TS had a change of −0.15 (Table 3). Figure 3 shows individual HSDS profiles over time, and indicates little impact on HSDS after the switch to Omnitrope, consistent with maintenance of growth during post-switch.

Fig. 3
figure 3

Height standard deviation score (HSDS) versus time from switch for all patients, and by indication. GHD Growth hormone deficiency, ISS idiopathic short stature, TS Turner syndrome

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Height Velocity

The mean HV for all patients at index date was 6.00 ± 1.93 cm/year. Over the 15-month post-switch period, mean HV decreased by 1.06 cm/year (Table 2). Within categories, the subjects’ mean HVs at the index date was 6.15 ± 2.13 cm/year, 5.90 ± 1.67 cm/year, and 5.71 ± 1.68 cm/year for the patients diagnosed with GHD, ISS, and TS, respectively. Those with GHD, ISS, and TS decelerated by 0.84 cm/year, 1.16 cm/year, and 1.62 cm/year, respectively (Table 3).

Height Velocity SDS

The mean HVSDS for all patients was 0.78 ± 2.90 over the 15-month post-switch period. During the initial 6 months, there was an increase for all patients in HVSDS (at 3 months HVSDS was 1.03 ± 2.86, at 6 months HVSDS was 1.16 ± 3.20); however, after 9 months the HVSDS for all patients declined slightly (Table 2; Fig. 4). This could be contributed to the advancing age. The patients mean HVSDS declined by an average of 0.52 over the 15-month post-switch period (Table 2; Fig. 4). The subjects’ mean body HVSDS at the index date within each category was 0.71 ± 3.08, 1.45 ± 2.56, and 0.13 ± 2.75 for the patients diagnosed with GHD, ISS and TS, respectively (Table 3; Fig. 4). Those with GHD declined, on average, by 0.33. Those with ISS declined, on average, by 0.59. Patients with TS declined, on average, by 0.85.

Fig. 4
figure 4

Height velocity standard deviation score for all patients

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Discussion

This present study has used real-world retrospective data to evaluate the impact of patients switching from a non-Omnitrope rhGH to Omnitrope in an US integrated healthcare system. Our findings indicate that such a switch can be conducted without negatively impacting the growth trajectories of the treated patients. This applies to the overall study population and also when considering the indication-specific subgroups (GHD, TS, ISS).

Patients were on a non-Omnitrope rhGH therapy for a mean duration of 4.6 years (SD ±1.24 years, minimum 1.52 years, maximum 5.84 years) and it has been shown in previous studies [16–20] that administration of growth hormone to children with GHD or ISS results in marked acceleration in linear growth, mostly during the first years of treatment. After 4–10 years of treatment, the HSDS increase wanes and does not differ significantly from the predicted score in the absence of therapy [16–20]. In this study, patients continued to grow in height and HSDS in all categories from index to 15 months post-switch. Results are expected and understandable given the age, overall duration of GH treatment, and pubertal status of the study population [16–20]. The mean HV for all patients in the study was 6.00 ± 1.93 cm/year over the 15-month post-switch period and is consistent with other reports of patients at similar durations of treatment [16, 17]. We recognize that the GH therapy dose that was used in TS patients pre- and post-switch was less than the recommended dose of 0.375 mg/kg/week. Nonetheless, patients’ individual height profiles were maintained after the switch. The overall growth rate for all the patients was similar with the similar GH dosages, and this may be due to how we identified the diagnosis codes for each patient in GH therapy. However, we reviewed the chart for each patient and tried to ensure that the diagnosis was categorized correctly.

Physicians are often faced with the need to change rhGH therapy, due to health plan and/or changes to a patient’s insurance, and this may be a cause of concern. Previous studies that have examined the impact of switching rhGH products have focused on parameters such as physician attitudes or the administrative burden on clinics, with the suggestion that patient care may be negatively impacted [21]. Alternatively, a comparative analysis of data from phase 3 studies demonstrated that switching rhGH therapy (from Genotropin to Omnitrope) has no impact on efficacy or safety in children with GHD [22]. More recently, a study from Sweden showed that patients with a range of pediatric growth disturbances could be successfully switched from Genotropin to Omnitrope, with no negative impact on growth and no serious or unexpected adverse drug reactions [23].

A limitation of our study is the retrospective nature of the analyses. Nevertheless, reporting of real-world data is of great value. We cannot exclude the possibility of inaccurate entry of data in the eMR system, although this possibility is equally likely to have occurred pre- and post-switch. We also required three visits that were 3 months apart during pre- and post-switch; however, some visits did not fall into the exact time position. We interpolated the data for some of these time positions using the closest height measurements before and after the time position of need, and calculated the height point.

Conclusion

This study used real-world retrospective data to examine the impact of switching from a non-Omnitrope rhGH to Omnitrope. The study demonstrated that patients continued to grow without alteration in their growth trajectories and can therefore be switched from a non-Omnitrope rhGH to Omnitrope without any negative impact on their growth. Our findings should be a useful resource for physicians who are faced with the possibility of switching rhGH therapy.