Abstract
Since 2010, the European Medicines Agency (EMA) has provided access to clinical study reports (CSRs). We requested CSRs for randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs) in cancer patients from EMA and identified RCT publications with literature searches. We assessed CSR availability and completeness, the impact of unreported and unpublished data obtained from CSRs on the effects of ESAs on quality of life (QoL) of cancer patients, and discrepancies between data reported in the public domain and in CSRs. We used random-effects meta-analyses to evaluate the effect of ESAs on QoL measured with Functional Assessment of Cancer Therapy-Anemia (FACT-An), FACT-Fatigue (FACT-F) and FACT-Anemia Total (FACT-An Total) stratified by data source and the impact of discrepancies on QoL, mortality, adverse events, and clinical effectiveness outcomes. We identified 94 eligible RCTs; CSRs or other study documentation were available for 17 (18%) RCTs at EMA. Median report length was 1,825 pages (range 72–14,569). Of 180 outcomes of interest reported in the EMA documentation, 127 (71%) were publicly available. For 80 of those (63%) we noted discrepancies, but these had little impact on the pooled effect estimates. Of 27 QoL outcomes reported in the CSRs, 17 (63%) were unpublished. Including six unpublished comparisons (pooled mean difference [MD] 0.20; 95% confidence interval [CI] -1.93, 2.33) reduced the pooled effect of ESAs for FACT-An from MD 5.51 (95% CI 4.20, 6.82) in published data to MD 3.21 (95% CI 1.38, 5.03), which is below a clinically important difference (defined as MD ≥4). Effects were similar for FACT-F and FACT-An Total. Access to CSRs from EMA reduced reporting biases for QoL outcomes. However, EMA received documentation for a fraction of all RCTs on effects of ESAs in cancer patients. Additional efforts by other agencies and institutions are needed to make CSRs universally available for all RCTs.
Highlights
Publication and outcome reporting biases are threats to the validity of evidence synthesis and health care decision-making [1,2,3,4,5,6,7]
From literature searches we identified 92 randomized controlled trial (RCT); no additional RCTs were identified through searches of trial registries
Including the unpublished data from the European Medicines Agency (EMA) documentation reduced the pooled estimate to mean difference (MD) 3.21, which is below the threshold of a clinically important difference for Functional Assessment of Cancer Therapy-Anemia (FACT-An)
Summary
Publication and outcome reporting biases are threats to the validity of evidence synthesis and health care decision-making [1,2,3,4,5,6,7]. Clinical study reports (CSRs) might serve as more complete data sources than publications in medical journals [13,14,15], and, assist in the reduction of reporting biases. Since 2010, the European Medicines Agency (EMA) has followed a policy on access to documents that affords wider access to documents held by that agency than before [16]. It allows access to CSRs and business-related documents unless there is a need to respect arrangements with regulators outside the European Union (EU) or international organizations, or to protect the privacy and integrity of natural or legal persons
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