title: The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies.
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.
authors.affiliation: Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Statler
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Department of Pharmacy, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Siebenaller
authors.affiliation: Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Gerds
authors.affiliation: Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kalaycio
authors.affiliation: Center for Ethics, Humanities and Spiritual Care, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kodish
authors.affiliation: Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pharmacy, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D006321:Heart / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D016015:Logistic Models; D016032:Randomized Controlled Trials as Topic
chemical_list: D000970:Antineoplastic Agents