Pharmacology

The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies

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Abstract

To minimize adverse events (AEs) unrelated to drugs and maximize the likelihood of drug approvals, eligibility criteria for randomized controlled trials (RCTs) may be overly restrictive. The purpose of this study was to determine if RCTs in hematologic malignancies exclude patients irrespective of known toxicities or observed AEs. MEDLINE was searched from 1/2010 to 1/2015 for RCTs published in high-impact journals. Of 97 trials, 33% were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndromes or myelofibrosis. Expected toxicities at thresholds of 10%, 5% and <5% were not correlated with cardiac, hepatic or renal eligibility criteria (logistic regression). To explore this lack of correlation we tested the concordance of expected toxicities and eligibility criteria using a modified version of McNemar’s test: at each threshold, hepatic, renal and cardiac expected toxicities were significantly discordant with eligibility criteria. Hepatic and renal eligibility criteria were also not correlated with observed AEs, P=0.69 and P=0.77, respectively, but a significant correlation was detected between cardiac eligibility criteria and observed AEs, P=0.02. Thus, the analyzed RCTs excluding patients with organ dysfunction do not reflect expected toxicities, based on prescription drug labels/prior experience, or reported AEs on the trials.

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Acknowledgements

Dr Sekeres is funded, in part, by the Edward P Evans Foundation.

Author information

Correspondence to M A Sekeres.

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The authors declare no conflict of interest.

Additional information

This study has been presented, in part, at the 2015 American Society of Hematology annual meeting as an oral presentation on 7 December 2015 in Orlando, FL, USA.

Supplementary Information accompanies this paper on the Leukemia website

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Statler, A., Radivoyevitch, T., Siebenaller, C. et al. The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies. Leukemia 31, 1808–1815 (2017) doi:10.1038/leu.2016.374

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