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Evaluating Dose Ratio of Subcutaneous to Intravenous Immunoglobulin Therapy Among Patients With Primary Immunodeficiency Disease Switching to 20% Subcutaneous Immunoglobulin Therapy
Girishanthy Krishnarajah, MPH, MBA/MS, PhD; Jee-Yeon K. Lehmann, PhD; Brian Ellman, MBA; Rachel H. Bhak, MS; Maral DerSarkissian, PhD; Deane Leader, Jr, PhD, MBA; Ann L. Bullinger, PharmD; and Mei

Evaluating Dose Ratio of Subcutaneous to Intravenous Immunoglobulin Therapy Among Patients With Primary Immunodeficiency Disease Switching to 20% Subcutaneous Immunoglobulin Therapy

Girishanthy Krishnarajah, MPH, MBA/MS, PhD; Jee-Yeon K. Lehmann, PhD; Brian Ellman, MBA; Rachel H. Bhak, MS; Maral DerSarkissian, PhD; Deane Leader, Jr, PhD, MBA; Ann L. Bullinger, PharmD; and Mei
A total of 278 patients met the inclusion criteria for the study; baseline characteristics are reported in Table 1. The study population was 66.2% female, and mean age and weight were 38.6 years (SD, 21.6; median, 42.0; IQR, 17.5-57.5) and 61.3 kg (SD, 36.0; median, 58.0; IQR, 35.5-79.0). Provider locations were similarly distributed across all geographic regions, with the highest proportion of providers in the South (30.6%) and Northeast (27.7%) regions. The most common PI diagnosis was immunodeficiency of humoral immunity (ICD-9-CM 279.0 and ICD-10-CM D83, 80.2%), followed by diagnosis of disorders involving the immune system (ICD-9-CM 279, 12.9%). Most shipped prescriptions were prescribed by providers specializing in allergy and immunology (81.3%), followed by pediatrics (9.7%). More than 80% of patients were covered by a commercial payer; approximately 20% of patients were covered by a federal payer.

Median Dose Ratios Over Time

Figure 2 presents the median Hizentra 20% SCIG-to-IVIG dose ratio for each 2-month period following the patients’ switch date. The initial median (IQR) Hizentra 20% SCIG-to-IVIG dose ratio was 1.14:1 (0.92:1-1.45:1) at 0 to 2 months post switch, a level lower than the dose ratio of 1.37:1 specified in the current US prescribing information. The median dose ratio was 1.09:1 (0.79:1-1.36:1) at 2 to 4 months and stabilized to 1.05:1 (0.75:1-1.34:1) at 4 to 6 months and 1.05:1 (0.70:1-1.34:1) 6 to 8 months post switch. As shown in Table 2, median dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were all statistically significantly different from the median dose ratio at 0 to 2 months post switch (all P <.001).

Results From Sensitivity Analysis Excluding Pediatric Patients

A total of 25 pediatric patients younger than 8 years of age were excluded in the sensitivity analysis sample. As shown in Figure 3, results from the sensitivity analysis were nearly identical to those from the main analysis, demonstrating that the main study results were robust to the assumption of constant patient weight over time. The initial median (IQR) Hizentra 20% SCIG-to-IVIG dose ratio excluding the pediatric population was 1.15:1 (0.88:1-1.45:1) at 0 to 2 months post switch. Median dose ratios were 1.09:1 (0.78:1-1.37:1) at 2 to 4 months, 1.06:1 (0.74:1-1.34:1) at 4 to 6 months, and 1.07:1 (0.70:1-1.34:1) at 6 to 8 months post switch. As observed in the main analysis, the median dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were all statistically significantly different from the median dose ratio at 0 to 2 months post switch (all P <.001).

Discussion

Results from this study of real-world US data indicate that many patients switching to 20% SCIG (Hizentra) from IVIG began treatment at dose ratios lower than the Hizentra 20% SCIG-to-IVIG dosing ratio of 1.37:1 recommended in the current US 20% SCIG (Hizentra) prescribing information. The median dose ratio subsequently reached approximately 1.1:1 after 2 months post switch and remained relatively stable through 8 months post switch. The median dose ratio at 0 to 2 months was statistically significantly different from dose ratios at later bimonthly intervals (2 to 4, 4 to 6, and 6 to 8 months). Hence, patients receive 20% SCIG (Hizentra) at a dose that is approximately equivalent to their IVIG dose, as recommended in the EU. These results are not surprising, because previous research has shown that 20% SCIG (Hizentra) is well-tolerated and effective in doses equivalent to IVIG. In fact, in 1 of the first studies of 20% SCIG (Hizentra), it was stated that a dose ratio of 1.53:1 may not be necessary, because doses of SCIG that were equivalent to previous IVIG doses resulted in a 17.7% increase in serum IgG levels.11,13 Furthermore, stabilization of the dose ratio at approximate equivalency is consistent with reports from PI clinical experts on their approach to management.17,18 Because the FDA recommends that SCIG doses be modified based on the patient’s clinical condition, results from this study may reflect the fact that similar doses of IVIG and SCIG are prescribed to reduce the rate of infection in patients with PI.

The conclusions of this study also held for the sensitivity analysis excluding pediatric patients from the study sample. Since the dose of 20% SCIG (Hizentra) is expected to increase over time with increasing weight for pediatric patients, it is expected that the dose ratio would also increase over time. However, the opposite trend was observed, and potential changes in patient weight did not impact stabilization of the postswitch dose ratio to approximately 1.1:1. 

Real-world dosing evidence presented in this study may also have implications on the expected costs of treatment associated with 20% SCIG (Hizentra). Although 20% SCIG (Hizentra) is more costly than IVIG, it has been shown to be cost-effective or cost-saving at a Hizentra 20% SCIG-to-IVIG dose ratio of 1:1 and cost-saving even at a dose ratio of 1.5:1 as a result of lower healthcare resource utilization and, therefore, lower costs for hospital care.19 The need for medical supervision and administration of IVIG infusions at healthcare centers is one of the main drivers of the cost differences between IVIG and SCIG treatment. A number of international studies have shown that switching from IVIG to SCIG also reduces healthcare costs incurred by payers as a result of decreased hospital personnel labor costs, increased healthcare personnel productivity, and less use of healthcare facilities.20-22 The convenience of administering SCIG at home, avoiding time spent at infusion centers, and reduced productivity loss resulting from short infusion times also provides indirect cost savings to patients.23

Improvements in patient quality of life are observed among pediatric and adult patients who switch from IVIG to SCIG, and dose ratios of approximately 1:1 are likely to be sufficient to achieve these positive outcomes.24 Specifically, patients treated with home-based SCIG reported improved treatment satisfaction, greater freedom and flexibility, and better school and social functioning among children.23 Given patient preference for home therapy, equal efficacy of SCIG and IVIG therapy in protecting against infections, and the relative safety of SCIG administration, it is not surprising that 90% of patients who switched from IVIG to SCIG therapy in a previous study remained on SCIG and 95% of newly diagnosed patients who chose SCIG over IVIG remained on SCIG.25

Thus, in addition to showing that the dose of 20% SCIG (Hizentra) needed to achieve positive clinical and quality-of-life outcomes is lower than the level currently recommended in the US, the potential implications of the lower, real-world dose ratio include reduced direct and indirect costs. These cost savings are certainly a benefit to patients and payers.

This analysis of real-world prescription data suggests that, for most PI patients, stable dose ratios close to 1:1 were achieved after 2 months following the switch, providing economic benefits to patients and lower costs to payers. As such, our findings indicate the current prescribing information–recommended dose ratio of 1.37:1 may be excessive and result in higher drug costs to the patient than necessary. Additional research is needed to confirm the results of our study.

Limitations

This study has several limitations. First, data on patient weight was not available for all patients and thus could not be factored into the calculation of dose ratios. Since prescribed dose for IVIG and SCIG therapy depend on weight, changes in weight over time may potentially affect dose ratios and render monthly doses over time incomparable. However, exclusion of pediatric patients, whose weight is likely to be the least stable, demonstrated that the same conclusions from the main study population hold, suggesting that study results were robust to potential changes in weight.

Second, the calculated doses for 20% SCIG (Hizentra) and IVIG are based on volume shipped and not volume prescribed or consumed by the patient, because this information is not regularly available from SP shipment data, to which this study was limited. Thus, it was assumed that the volume shipped was equal to the volume administered to the patient. However, a method that estimated monthly dose by calculating daily doses first was applied to ensure that dose estimates were as accurate as possible. The availability of additional data fields may enhance the ability to address objectives of the current study. Currently, few datasets would allow for such an investigation. In addition, the nonuniformity of shipment intervals and missing dose ratios in consecutive 2-month periods (addressed using the last observation carried forward imputation method, which may increase bias) are also limitations of this study.

Lastly, as with all retrospective observational studies, these results may be subject to selection bias. Data on the patient’s clinical condition (e.g., comorbidities and infection history) prior to and following switch, IgG serum levels, and clinical outcomes were lacking from the SP database used in this study. Although the objective of this analysis was to calculate monthly dose ratios, these interesting findings may warrant a future study to examine clinical and quality-of-life outcomes associated with different dose ratios, and to examine the economic impact of lower dose ratios.

Conclusions

Real-world data show that patients switching from IVIG began SCIG therapy with 20% SCIG (Hizentra) at dose ratios lower than the current prescribing information–recommended dose ratio in the US. Stabilization of the Hizentra 20% SCIG-to-IVIG dose ratio close to 1:1 is consistent with reports of clinical management of PI and with the dosing ratio used in the EU. In previous research, serum IgG levels with SCIG have been shown to be higher than with IVIG, and this raises the possibility that the dose adjustment factor recommended in the current prescribing information in the US may be too high or unnecessary.

Author affiliation: Analysis Group, Inc; Boston (RHB, MD, MSD, BE, JKL); CSL Behring, LLC; King of Prussia, PA (ALB, GK, DL).
Funding source: This supplement was sponsored by CSL Behring, LLC.
Author disclosures: Dr Krishnarajah reports serving as a paid advisory board member for CSL Behring, employment with CSL Behring, and stock ownership in CSL Behring and GSK. Ms Bhak, Dr DerSarkissian, Dr Duh, Mr Ellman, and Dr Lehmann report employment with Analysis Group. Dr Bullinger reports employment with CSL Behring. Dr Leader reports employment with CSL Behring at the time of this study.
Authorship information: Concept and design (RHB, ALB, MD, MSD, BE, GK, JKL); acquisition of data (DL); analysis and interpretation of data (RHB, ALB, MD, MSD, BE, GK, DL, JKL); drafting of the manuscript (RHB, MD, BE, GK, JKL); critical revision of the manuscript for important intellectual content (RHB, ALB, MD, MSD, BE, GK, JKL); statistical analysis (RHB, MD, BE, DL, JKL); obtaining funding (MSD); and supervision (MSD).
Address correspondence to: Girishanthy Krishnarajah, MPH, MBA/MS, PhD; CSL Behring, 1020 1st Avenue, King of Prussia, PA. E-mail: shanthy
.krishnarajah@cslbehring.com.
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