title: Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.
abstract: In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.
authors.affiliation: Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, CA, UCLA School of Medicine, Los Angeles, CA 90509, USA. roger@emedharbor.edu
authors.forename: R J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: D A
authors.initials: DA
authors.lastname: Berry
authors.forename: H
authors.initials: H
authors.lastname: Cryer
authors.forename: N
authors.initials: N
authors.lastname: Fost
authors.forename: R
authors.initials: R
authors.lastname: Krome
authors.forename: G R
authors.initials: GR
authors.lastname: Washington
authors.forename: J
authors.initials: J
authors.lastname: Houghton
authors.forename: J W
authors.initials: JW
authors.lastname: Blue
authors.forename: R
authors.initials: R
authors.lastname: Bechhofer
authors.forename: T
authors.initials: T
authors.lastname: Cook
authors.forename: M
authors.initials: M
authors.lastname: Fisher
mesh_terms: D001241:Aspirin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D016638:Critical Illness / Q000401:mortality* / Q000628:therapy*; D005260:Female; D005500:Follow-Up Studies; D006454:Hemoglobins / Q000008:administration & dosage*; D006801:Humans; D007258:Informed Consent; D015601:Injury Severity Score; D008297:Male; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D012151:Resuscitation / Q000592:standards; D012771:Shock, Hemorrhagic / Q000209:etiology / Q000401:mortality* / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D006454:Hemoglobins; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin