Session Information
Date: Tuesday, October 23, 2018
Title: 5T109 ACR Abstract: RA–Treatments V: Beyond Individual Compounds (2874–2879)
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose:
Intention-to-treat (ITT) principle is recommended to analyze randomized controlled trials (RCTs). It entails analyzing all subjects per the assigned group at randomization to avoid treatment effect estimation bias. Missing outcome data in RCTs can compromise results1 and its wrong handling may cause bias. Single imputation methods e.g. “last observation carried forward (LOCF)” have unrealistic assumptions and discount the uncertainty of imputation2. Sensitivity analyses are recommended to assess robustness of such assumptions 2. We studied RCTs of rheumatoid arthritis (RA) for ITT use, missing outcome data handling, and sensitivity analysis usage. Trends between 2006 and 2016 were analyzed.
Methods:
MEDLINE and Cochrane Central Register of Controlled Trials database were searched to identify parallel-design, non-phase-1, English language, original RA RCTs of drug therapy with clinical primary outcome(s) published in 2006 and 2016. The study RCTs were assessed by two reviewers. ITT analysis was defined when all randomized subjects were included in the final analysis for the primary outcome(s). A modified ITT (mITT) allowed exclusion of one or more of the following: those found non-eligible after randomization, those who never received study intervention, and those without baseline or any post-baseline assessment 3. All other exclusions were classified as inadequate.
Results:
80 RCTs, 36 from 2006 and 44 from 2016, were eligible (Table 1). 48/69 (69.5%) RCTs had > 10% and 17/69 (24.6) had >20% missing data. RCTs doing ITT or mITT analyses enrolled more subjects (p < .001) but had similar completion rates (p = .734). Missing data of >10% was more in comparator arm vs. experimental intervention arm [16 (25.4%) vs. 3 (4.8%)]. RCTs performing ITT analyzed 100% subjects. Median (IQR) % analyzed for mITT RCTs was 98.8 (97.5-99.5) and inadequate analysis RCTs was 88.6 (81.7-92.1).LOCF was the most used imputation method. Utilization of ITT or mITT analysis from 2006 to 2016 was similar [23/34 (67.6%) vs 25/42 (59.5%), p = .465]. Only 42.9% and 57.1% RCTs reporting ITT analysis actually performed one in 2006 and 2016 respectively. Sensitivity analysis use between 2006 and 2016 was similarly low [6/36 (16.7%) vs 9/44 (20.5%), p = .666]. Only one 2006 RCT used the preferred imputation methods. Missing mechanisms and comparison of completers and dropouts were given by one RCT each.
|
Table 1. Comparison of 2006 and 2016 RCTs |
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|
Characteristics |
All (n = 80) |
Study year |
P |
|
|
2006 (n = 36) |
2016 (n = 44) |
|||
|
Funding source Non-profit Industry Both non-profit & industry Unspecified |
21 (26.3) 40 (50) 5 (6.3) 14 (17.5) |
8 (22.2) 20 (55.6) 3 (8.3) 5 (13.9) |
13 (29.5) 20 (45.5) 2 (4.5) 9 (20.5) |
.623 |
|
Experimental intervention Biologic Traditional DMARD Small molecule Other |
42 (52.5) 8 (10) 4 (9.1) 26 (32.5) |
19 (52.8) 5 (13.9) 0 (0) 12 (33.3) |
23 (52.3) 3 (6.8) 4 (9.1) 14 (31.8) |
.123 |
|
Efficacy* Positive Negative |
59 (80.8) 14 (19.2) |
28 (84.8) 5 (15.2) |
31 (77.5) 9 (22.5) |
.427 |
|
Study phase Phase 2 Non-phase 2/unspecified |
13 (16.3) 67 (83.8) |
3 (8.3) 33 (91.7) |
10 (22.7) 34 (77.3) |
.074 |
|
Total patient Median (IQR) |
(n = 76) 162 (74-326) |
(n = 34) 163 (53-367) |
(n = 42) 159 (79-311) |
.913 |
|
Patient percent completing study Median (IQR) |
(n = 69) 86.7 (79.8-91.4) |
(n = 31) 85.1 (71.5-92.3) |
(n = 38) 87.4 (81.5-91.3) |
.201 |
|
Patient percent analyzed for primary* outcome Median (IQR) |
(n = 73) 99.7 (97.1-100) |
(n = 32) 99.6 (97.3-100) |
(n = 41) 99.7 (96.9-100) |
.879 |
|
Analysis** ITT Modified ITT Completer/inadequate Unclear |
28 (36.8) 20 (26.3) 16 (21.1) 12 (15.8) |
12 (35.3) 11 (32.4) 4 (11.8) 7 (20.6) |
16 (38.1) 9 (21.4) 12 (28.6) 5 (11.9) |
.217 |
|
Amount of missing outcome data <5%, N (%) 5.1-10%, N (%) 10.1-20%, N (%) >20%, N (%) |
(n = 69) 8 (11.6) 13 (18.8) 31 (44.9) 17 (24.6) |
(n = 31) 1 (3.2) 8 (25.8) 13 (41.9) 9 (29.0) |
(n = 38) 7 (18.4) 5 (13.2) 18 (47.4) 8 (21.1) |
.116 |
|
Missing data handling method given*** N (%) |
(n = 79) 43 (54.4) |
(n = 36) 22 (61.1) |
(n = 43) 21 (48.8) |
.275 |
|
Stated using ITT or mITT** N (%) |
(n = 76) 48 (63.1) |
(n = 34) 23 (67.6) |
(n = 42) 25 (59.5) |
.465 |
|
Common methods to impute missing data, LOCF, N (%) Non-responder imputation, N (%) Baseline observation carried forward, N (%) |
(n = 80) 25 (31.3) 21 (26.3) 4 (5.0) |
(n = 36) 15 (41.7) 9 (25.0) 2 (5.6) |
(n = 44) 10 (22.7) 12 (27.3) 2 (4.5) |
.069 .818 .535 |
|
Performed sensitivity analysis N (%) |
(n = 80) 15 (18.8) |
(n = 36) 6 (16.7) |
(n = 44) 9 (20.5) |
.666 |
|
*N = 73, 4 RCTs excluded as safety was primary outcome and 3 as strategy trials with no a priori declared experimental intervention; **N = 76, 4 RCTs excluded as safety was primary outcome; ***One RCT had no missing data. |
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Conclusion:
Missing data is common and most RCTs have >10 % missing data. While most patients are in the final analysis, many RCTs apply ITT principle incorrectly, utilize inappropriate single imputation methods and do not specify missing data handling methods. Sensitivity analyses and mechanism of missingness reporting is very low. No significant changes were seen from 2006 to 2016.
References:
- O’Neill RT. Clin Pharmacol Ther. 2012;91:550-4
- Little RJ. N Engl J Med 2012;367:1355-60
- Dossing A. J Clin Epidemiol 2016;72:66-74
To cite this abstract in AMA style:
Aslam F, Torralba K, Khan NA. Comparison of Missing Data Reporting and Handling in Randomized Controlled Trials of Rheumatoid Arthritis Drug Therapy: A Snapshot Ten Years Apart [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/comparison-of-missing-data-reporting-and-handling-in-randomized-controlled-trials-of-rheumatoid-arthritis-drug-therapy-a-snapshot-ten-years-apart/. Accessed .« Back to 2018 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparison-of-missing-data-reporting-and-handling-in-randomized-controlled-trials-of-rheumatoid-arthritis-drug-therapy-a-snapshot-ten-years-apart/