Background
Methods
Strategy for the inclusion of RWE in the drug development process
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Step 1(a).(b).Perform NMAs sequentially in time to include each phase III trial separately in the meta-analysis of all earlier studies, and then finally include all RCTs together.(c).Extract ARR and standard error from the NMA to use in simulation of alternative development strategies.
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Step 2(a).Use estimates from the NMA based on the predictive distribution [19] to simulate the effects and confidence interval of a future alternative phase III trial (by sampling from a negative binomial distribution).(b).Assess how many patients will be needed to execute a similar phase III trial with sufficient power (90%), whilst the probability of falsely claiming effectiveness remains low (< 5%).
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Step 3
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Compare the size of the original trial with the size of the simulated trial.
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Step 4(a).Investigate whether the original trial could have been executed successfully with the alternative number of patients by analysing the original trial with a lower number of patents.(b).Using the (lower) number of patients obtained from the simulated trials, run clinical trial simulations assuming the treatment effects are as observed in the reported clinical trials.(c).Assess power and false positive rate.
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Step 5
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Include the size and relative effect estimates of simulated trials instead of the original trial results in an NMA to investigate whether or not there is a difference in the totality of evidence of effectiveness between the original NMA and the NMA based on simulated results.
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Illustrative example
Study | Treatments | No. of patients (N) | Primary outcome | Relevant secondary outcomes | Power/significance level |
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Phase II [17] | Placebo or fingolimod 1.25 mg or fingolimod 5 mg | 281 | Hamburg Quality of Life Questionnaire (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) | Not published | Not published |
TRANSFORMS [18] | Interferon beta-1a or fingolimod 0.5 mg or fingolimod 1.25 mg | 1292 | Annualised relapse rate | Change in Expanded Disabiity Status Scale (EDSS) score | 90%/5% (two-sided) |
FREEDOMS [20] | Placebo or fingolimod 0.5 mg or fingolimod 1.25 mg | 1272 | Annualised relapse rate | Change in EDSS score | Power not published/5% (two-sided) |
FREEDOMS II [21] | Placebo or fingolimod 0.5 mg or fingolimod 1.25 mg | 1083 | Annualised relapse rate | Change in EDSS score | 90%/5% (two-sided) |
Study | Treatments | No. of subjects (N) | No. of Relapses | Person years | EDSS |
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Lanzillo (2012) [39] | Natalizumab | 42 | 10 | 42 | 3.5 |
Rebif 44 | 42 | 23 | 42 | ||
Limmroth (2007) [40] | Avonex | 1094 | 1116 | 2188 | 2.62 |
Betaferon | 1034 | 1075 | 2068 | ||
Rebif 22 | 555 | 588 | 1110 | ||
Rebif 44 | 185 | 233 | 370 | ||
Halpern (2011) [41] | Natalizumab | 288 | 21 | 72 | |
Avonex | 151 | 7 | 38 | ||
Rebif 22 | 329 | 22 | 82 | ||
Betaferon | 144 | 11 | 36 | ||
Glatiramer acetate | 469 | 25 | 117 | ||
Patti (2006) [42] | Betaferon | 114 | 137 | 570 | 2.2 |
Avonex | 37 | 50 | 185 | ||
Rebif 22 | 17 | 35 | 85 | ||
Río (2005) [43] | Placebo | 107 | 288 | 356 | 2.73 |
Glatiramer acetate | 101 | 204 | 334 | ||
Haas and Firzlaff (2005) [44] | Avonex | 79 | 109 | 158 | 2.2 |
Betaferon | 77 | 123 | 154 | 2.28 | |
Glatiramer acetate | 79 | 56 | 158 | 1.98 | |
48 | 59 | 96 | 2.36 | ||
Khan et al. (2001) [45] | Placebo | 15 | 23 | 23 | 2.63 |
Avonex | 34 | 41 | 51 | 2.71 | |
Betaferon | 34 | 28 | 51 | 2.6 | |
Glatiramer acetate | 39 | 29 | 59 | 2.64 | |
Trojano et al. (2003) [46] | Betaferon | 209 | 136 | 418 | 2.5 |
Avonex | 169 | 120 | 338 | 2.4 | |
Carra et al. (2003) [47] | Avonex | 26 | 14 | 35 | 2.02 |
Rebif 44 | 20 | 2 | 27 | 2.08 | |
Betaferon | 20 | 11 | 27 | 3.31 | |
Glatiramer acetate | 30 | 8 | 40 | 2.45 |
Network diagram
Network-meta analysis methods
Clinical trial simulations
Software
Results
Results of NMA
Placebo | Nataluzimab | Fingolimod 1.25 | Fingolimod 0.5 | Avonex | Rebif 22 | Rebif 44 | Copaxone | Betaferon | |
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Placebo | 0.314 (0.03) | 0.462 (0.03) | 0.423 (0.03) | 0.832 (0.06) | 0.727 (0.07) | 0.679 (0.05) | 0.659 (0.04) | 0.670 (0.05) | |
Nataluzimab | 0.407 (0.07) | 1.488 (0.20) | 1.361 (0.20) | 2.677 (0.30) | 2.336 (0.30) | 2.183 (0.30) | 2.120 (0.30) | 2.157 (0.3) | |
Fingolimod 1.25 | 0.455 (0.05) | 1.150 (0.23) | 0.918 (0.08) | 1.808 (0.17) | 1.581 (0.19) | 1.476 (0.15) | 1.433(0.14) | 1.458 (0.15) | |
Fingolimod 0.5 | 0.413 (0.05) | 1.045 (0.22) | 0.916 (0.12) | 1.977 (0.19) | 1.728 (0.21) | 1.614 (0.17 | 1.567 (0.16) | 1.594 (0.17) | |
Avonex | 0.783 (0.07) | 1.977 (0.36) | 1.742 (0.24) | 1.920 (0.27) | 0.877 (0.09) | 0.818 (0.06) | 0.795 (0.07) | 0.808 (0.07) | |
Rebif 22 | 0.766 (0.08) | 1.933 (0.36) | 1.706 (0.26) | 1.880 (0.30) | 0.982 (0.10) | 0.939 (0.08) | 0.913 (0.10) | 0.929 (0.10) | |
Rebif 44 | 0.7482 (0.08) | 1.887 (0.35) | 1.666 (0.26) | 1.837 (0.30) | 0.959 (0.10) | 0.983 (0.11) | 0.974 (0.07) | 0.991 (0.09 | |
Copaxone | 0.601 (0.05) | 1.517 (0.28) | 1.338 (0.19) | 1.474 (0.21) | 0.771 (0.07) | 0.790 (0.09) | 0.809 (0.09) | 1.019 (0.07) | |
Betaferon | 0.700 (0.07) | 1.768 (0.32) | 1.559 (0.22) | 1.718 (0.25) | 0.897 (0.07) | 0.920 (0.09) | 0.943 (0.1) | 1.170 (0.11) |
Results of clinical trial simulations
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Option I (corresponding to alternative I Fig. 7). This option illustrates the original strategy to execute the studies with a similar number of patients. Using RWE to design the TRANSFORMS, the subsequent studies were assumed to require a similar number of patients. The timelines show that using RWE to design the clinical programme could result in a savings of 6 or 7 months on each trial.
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Option II (corresponding to alternative II in Fig. 7). Clinical trial simulations of the FREEDOMS trials showed that the FREEDOMS II trial required a similar number of patients as the FREEDOMS trial (567 in total). In this option, the resulting savings would be remarkable: 6 months for TRANSFORMS, 11 months for FREEDOMS and 16 months for FREEDOMS II.
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Option III (combining alternatives I and II). Based on the number of patients needed to execute the alternative FREEDOMS II trial (mainly a North American population), the FREEDOMS II trial could be executed as a cohort of the FREEDOMS trial. This implies that the FREEDOMS II trial would not be required. The single trial would have more than sufficient power to analyse the patients recruited in FREEDOMS and the North American cohort consisting of 189 patients per arm (567 in total). The combined FREEDOMS trials could require a total of 1134 patients (2 × 567), and the FREEDOMS II trial would not be required as a separate trial, whilst the alternative FREEDOMS trial would still be marginally smaller than the reported trial with 1272 patients randomised.
Placebo | Nataluzimab | Fingolimod 1.25 | Fingolimod 0.5 | Avonex | Rebif 22 | Rebif 44 | Copaxone | Betaferon | |
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Placebo | 0.319 (0.05) | 0.519 (0.05) | 0.465 (0.05) | 0.916 (0.09) | 0.783 (0.10) | 0.706 (0.07) | 0.667 (0.06) | 0.686 (0.07) | |
Nataluzimab | 0.420 (0.08) | 1.666 (0.31) | 1.492 (0.28) | 2.940 (0.54) | 2.370 (0.54) | 2.265 (0.42) | 2.140 (0.39) | 2.157 (0.41) | |
Fingolimod 1.25 | 0.497 (0.07) | 1.210 (0.28) | 0.901 (0.09) | 1.781 (0.22) | 1.437 (0.25) | 1.373 (0.20) | 1.297 (0.18) | 1.335 (0.19) | |
Fingolimod 0.5 | 0.448 (0.07) | 1.103 (0.26) | 0.913 (0.13) | 1.989 (0.25) | 1.606 (0.28) | 1.534 (0.22) | 1.450 (0.20) | 1.491 (0.22) | |
Avonex | 0.831 (0.08) | 2.039 (0.40) | 1.703 (0.27) | 1.886 (0.30) | 0.811 (0.13) | 0.774 (0.09) | 0.732 (0.09) | 0.753 (0.09) | |
Rebif 22 | 0.798 (0.10) | 1.957 (0.40) | 1.639 (0.30) | 1.814 (0.33) | 0.965 (0.11) | 0.920 (0.14) | 0.920 (0.14) | 0.945 (0.16) | |
Rebif 44 | 0.781 (0.10) | 1.914 (0.38) | 1.604 (0.29) | 1.776 (0.32) | 0.944 (0.11) | 0.987 (0.13) | 0.951 (0.10) | 0.980 (0.13) | |
Copaxone | 0.614 (0.06) | 1.507 (0.30) | 1.261 (0.21) | 1.396 (0.23) | 0.743 (0.08) | 0.777 (0.10) | 0.794 (0.10) | 1.033 (0.10) | |
Betaferon | 0.728 (0.08) | 1.788 (0.35) | 1.496 (0.25) | 1.656 (0.28) | 0.881 (0.08) | 0.921 (0.10) | 0.941 (0.11) | 1.193 (0.12) |