Missing data in randomized controlled trials testing palliative interventions pose a significant risk of bias and loss of power: a systematic review and meta-analyses

Abstract

ObjectivesTo assess the risk posed by missing data (MD) to the power and validity of trials evaluating palliative interventions.Study Design and SettingA systematic review of MD in published randomized controlled trials (RCTs) of palliative interventions in participants with life-limiting illnesses was conducted, and random-effects meta-analyses and metaregression were performed. CENTRAL, MEDLINE, and EMBASE (2009–2014) were searched with no language restrictions.ResultsOne hundred and eight RCTs representing 15,560 patients were included. The weighted estimate for MD at the primary endpoint was 23.1% (95% confidence interval [CI] 19.3, 27.4). Larger MD proportions were associated with increasing numbers of questions/tests requested (odds ratio [OR], 1.19; 95% CI 1.05, 1.35) and with longer study duration (OR, 1.09; 95% CI 1.02, 1.17). Meta-analysis found evidence of differential rates of MD between trial arms, which varied in direction (OR, 1.04; 95% CI 0.90, 1.20; I2 35.9, P = 0.001). Despite randomization, MD in the intervention arms (vs. control) were more likely to be attributed to disease progression unrelated to the intervention (OR, 1.31; 95% CI 1.02, 1.69). This was not the case for MD due to death (OR, 0.92; 95% CI 0.78, 1.08).ConclusionThe overall proportion and differential rates and reasons for MD reduce the power and potentially introduce bias to palliative care trials.

Clinical trials in palliative care: a systematic review of their methodological characteristics and of the quality of their reporting

“…Looking at our pooled results, there was a higher percentage of dropouts in intervention arm. Hussain et al [37] in a review on missing data in PC RCT reported a similar result with a high dropout rate in intervention arm. However, as we mentioned in results section there was a high level of heterogeneity between studies that didn’t allow to be conclusive in relation to this question.…”

What influenced people with chronic or refractory breathlessness and advanced disease to take part and remain in a drug trial? A qualitative study

“…The trial design was important, and attempts to minimise burden were viewed favourably by participants. This is an important consideration as missing data in trials has been shown to increase with the number of questionnaires/tests [17].…”

“…Reasons for attrition included a high symptom burden (21%), patient preference (15%), hospitalisation (10%), and death (6%) [16]. Attrition can lead to high levels of missing data, the level of which, in a recent systematic review of palliative care trials, was associated with study duration and an increasing number of study questionnaires and/or tests [17]. However, even for palliative care drug trials of short duration (4 weeks), attrition has been shown to be high, with only 40% of participants achieving the primary end point in a trial of pregabalin for cancerinduced bone pain [5].…”

What influenced people with chronic breathlessness and advanced disease to take part and remain in a drug trial? A qualitative study.

“…Reasons for attrition included a high symptom burden (21%), patient preference (15%), hospitalisation (10%), and death (6%) (16). Attrition can lead to high levels of missing data, the level of which, in a recent systematic review of palliative care trials, was associated with study duration and an increasing number of study questionnaires and/ or tests (17). However, even for palliative care drug trials of short duration (4 weeks) attrition has been shown to be high, with only 40% of participants achieving the primary end point in a trial of pregabalin for cancer induced bone pain (5).…”