Table 3.
Examples of RCTs conducted to demonstrate equivalence between G-CSF reference products and its biosimilars in breast cancer
| Paper | Reference G-CSF | Proposed biosimilar G-CSF | Patients randomized to treatment | Primary endpoint | Study power/sample size assumptions |
|---|---|---|---|---|---|
| Holmes FA, et al. J Clin Oncol. 2002;20(3):727–31 [35] |
Filgrastim (Neupogen®, Amgen) Pegfilgrastim (Neulasta®, Amgen) |
N/A | N = 310 (filgrastim, N = 156; pegfilgrastim, N = 154) | Mean DSN in cycle 1, (number of days with grade 4 neutropenia with an ANC < 0.5 × 109/L) |
Equivalence was assessed using an upper 97.5% one-sided confidence interval limit (95% two-sided) with an equivalence limit of < 1 day for the difference in mean DSN. Based on similar assumptions for the test, this would mean 90% power. |
| Holmes FA, et al. Ann Oncol. 2002;13: 903–9 [36] |
Filgrastim (Neupogen®, Amgen) Pegfilgrastim (Neulasta®, Amgen) |
N/A | N = 154 (filgrastim, N = 25; pegfilgrastim, N = 129) | Mean DSN in cycle 1, (number of days with grade 4 neutropenia with an ANC < 0.5 × 109/L) |
Equivalence was assessed using a two-sided 95% confidence interval with an equivalence limit of ± 1 day for the difference in mean DSN. For the dose groups comparison, assumptions presented gave a power of about 80% per group comparison with no adjustment of alpha. |
| Green MD, et al. Ann Oncol. 2003;14:29–35 [34] |
Filgrastim (Neupogen®, Amgen) Pegfilgrastim (Neulasta®, Amgen) |
N/A | N = 157 (filgrastim, N = 77; pegfilgrastim, N = 80) | Mean DSN in cycle 1, (number of days with grade 4 neutropenia with an ANC < 0.5 × 109/L) |
Sample size was based on a non-inferiority design, and the mean duration and standard deviation (SD) of severe neutropenia observed in the phase II study. Equivalence was assessed using an upper 97.5% one-sided confidence interval limit (95% two-sided) with an equivalence limit of < 1 day for the difference in mean DSN. The phase II publication only presented confidence intervals (not mean and SD) but it seems likely that 90% power was used. |
| Del Giglio A, et al. BMC Cancer 2008;8:332 [37] | Filgrastim (Neupogen®, Amgen) | Filgrastim (XM02, Teva) | N = 348 (reference filgrastim, N = 140; biosimilar filgrastim, N = 136; placebo N = 72) | Mean DSN in cycle 1, (number of days with grade 4 neutropenia with an ANC < 0.5 × 109/L) |
Equivalence was assessed using a two-sided 95% confidence interval with an equivalence limit of ± 1 day for the difference in mean DSN. Based on similar assumptions for the test, this would mean 90% power. |
| Waller CF, et al. Onkologie. 2010;33(10):504─11 [38] | Filgrastim (Neupogen®, Amgen) | Filgrastim (Nivestim®, Hospira) | N = 279 (reference filgrastim, N = 95; biosimilar filgrastim, N = 184) | Mean DSN (ANC < 0.5 × 109/L) in treatment cycle 1 |
Equivalence was assessed using a two-sided 95% confidence interval with an equivalence limit of ± 1 day for the difference in the adjusted mean DSN. Based on similar assumptions for the test, this would mean 90% power. |
| Buchner A, et al. Breast Cancer Res Treat. 2014; 148:107–16 [39] | Pegfilgrastim (Neulasta®, Amgen) | Lipegfilgrastim (XM22, Teva) | N = 208 (pegfilgrastim, N = 54; lipegfilgrastim 3 mg, N = 53; lipegfilgrastim 4.5 mg, N = 51; lipegfilgrastim 6 mg, N = 50) | Mean DSN (number of consecutive days from ANC < 0.5 × 109/L to ≥ 0.5 × 109/L) during cycle 1 |
The number of patients per treatment group was not based on formal statistical sample size calculations but was considered adequate to allow for determination of an optimal lipegfilgrastim dose for phase III clinical studies. Comparison of DSN to show non-inferiority was performed post hoc and the study was not powered for this analysis but 95% confidence limits were used for the difference in mean duration with an equivalence margin of ± 0.5 day. For the dose groups comparisons, assumptions presented led to a power of about 80% per group comparison with no adjustment of alpha. |
| Blackwell K, et al. Ann Oncol. 2015;26:1948–53 [18] | Filgrastim (Neupogen®, Amgen) | Filgrastim (EP2006, Sandoz) | N = 218 (reference filgrastim, N = 54; biosimilar filgrastim, N = 54; reference then biosimilar, N = 55; biosimilar then reference, N = 55) | Mean DSN (number of consecutive days from ANC < 0.5 × 109/L to ≥ 0.5 × 109/L) during cycle 1 | Assuming an expected mean difference in DSN of 0.25 days with a common standard deviation of 1.5 days, a 10% dropout rate and a non-inferiority margin of − 1 day, 96 patients per group (biosimilar or reference) were required to have 90% power for showing non-inferiority based on a one-sided 97.5% CI. |
| Blackwell K, et al. Oncologist 2016; 21:789–94 [40] | Pegfilgrastim (Neulasta®, Amgen) | Pegfilgrastim (LA-EP2006, Sandoz) | N = 308 (reference pegfilgrastim, N = 153; biosimilar pegfilgrastim, N = 155) | Mean DSN (number of consecutive days from ANC < 0.5 × 109/L to ≥ 0.5 × 109/L) during cycle 1 | A sample size of 302 patients was considered sufficient to achieve 90% power for testing of equivalence (two one-sided tests) at the 2.5% significance level, assuming no difference in mean DSN between treatments with a common SD of 1.6 days. |
| Harbeck N, et al. Future Oncol. 2016;12(11):1359–67 [41] | Pegfilgrastim (Neulasta®, Amgen) | Pegfilgrastim (LA-EP2006, Sandoz) | N = 316 (reference pegfilgrastim, N = 149; biosimilar pegfilgrastim, N = 146) | Mean DSN (number of consecutive days from ANC < 0.5 × 109/L to ≥ 0.5 × 109/L) during cycle 1 | A sample size of 302 patients was considered sufficient to achieve 90% power for testing of equivalence (two one-sided tests) at the 2.5% significance level, assuming no difference in mean DSN between treatments with a common standard deviation (SD) of 1.6 days. |
| Hegg R, et al. Clinics (Sao Paulo). 2016;71(10):586–92 [42] | Filgrastim (Granulokine®, Roche) | Filgrastim (Fiprimas®, Eurofarma) | N = 217 (reference filgrastim, N = 108; biosimilar filgrastim, N = 109) | Rate of grade 4 neutropenia during cycle 1 | Sample size was calculated using the historical incidence of grade 4 neutropenia after the first chemotherapy cycle. This was 73–83% in studies involving the two eligible chemotherapy regimens. Considering a one-tailed alpha of 5% and a statistical power of 80% for the study to obtain a maximum absolute difference of 15% in the rate of grade 4 neutropenia between the two groups, and assuming that this rate would be 80% in the control group, 88 patients should be included in each study group. Assuming a dropout rate of approximately 20%, 110 patients were anticipated in each arm, for a total of 220 patients. |
| Waller CF et al. 2017. European CanCer Organization (ECCO) 2017 European Cancer Congress. January 27–30, 2017, Amsterdam, Netherlands [43] | Pegfilgrastim (Neulasta®, Amgen) | Pegfilgrastim (MYL-1401H, Mylan) | N = 164 (reference pegfilgrastim, N = 67; biosimilar pegfilgrastim, N = 127) | DSN in cycle 1 (days with absolute neutrophil count [ANC] < 0.5 × 109/L) |
Equivalence was assessed using a two-sided 95% confidence interval with an equivalence limit of ± 1 day for the difference in the adjusted mean DSN. Based on similar assumptions for a test, this would mean 90% power. |
The table also includes RCTs comparing reference pegfilgrastim with reference filgrastim in patients with breast cancer. Neupogen® and Neulasta® are registered trademarks of Amgen; Nivestim® is a registered trademark of Hospira; Granulokine® is a registered trademark of Amgen/Roche; Fiprimas® is a registered trademark of Eurofarma.
N/A not applicable