title: Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.
abstract: BACKGROUND
  In 2000, the US Food and Drug Administration approved CroFab(®) Crotalidae Polyvalent Immune Fab, ovine (FabAV), which had received orphan drug designation, for use in patients with minimal to moderate North American crotaline envenomations including copperhead snakes. As existing evidence on the effectiveness of FabAV for this indication is limited, wide practice variation in its use exists. In order to provide more definitive clinical evidence as to the role of this treatment, a new randomized, placebo-controlled trial of FabAV specifically for copperhead bites was initiated.
  
  
  OBJECTIVE
  In light of the existing US Food and Drug Administration approval, ethical considerations of participation in this trial have been raised. We discuss the ethical principles pertinent to this randomized, placebo-controlled trial with placebo arm. We apply an accepted framework for ethical research to this trial. Due to the evidence gap in the literature, wide-ranging treatment recommendations by medical experts, and broad practice variation, clinical equipoise exists in the treatment of copperhead envenomation with FabAV. The impact of this clinical equipoise on the value and scientific validity of the trial is discussed. The trial's risk-benefit ratio is also considered. Potential risks to the patients are minimized as the protocol includes a plan for rescue therapy in the event that patients progress to severe envenomation symptoms. Overall, risks are further minimized by the inclusion of an interim analysis with stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial.
  
  
  CONCLUSIONS
  Although a post-marketing clinical study of this nature is unusual for an approved indication, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects.
authors: Division of Emergency Medicine, Department of Surgery, Duke University, Durham, NC, USA gerar001@mc.duke.edu.
authors: Charles J
authors: CJ
authors: Gerardo
authors: Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, CO, USA Division of Medical Toxicology, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: Eric J
authors: EJ
authors: Lavonas
authors: Trent Center for Bioethics, Humanities, & History of Medicine, Duke University Medical Center, Department of Pediatrics, Duke University, Durham, NC, USA.
authors: Ross E
authors: RE
authors: McKinney
mesh_terms: D017836:Agkistrodon; D000818:Animals; D000997:Antivenins / Q000627:therapeutic use*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D009965:Orphan Drug Production; D015990:Placebo Effect; D011358:Product Surveillance, Postmarketing; D016032:Randomized Controlled Trials as Topic / Q000941:ethics*; D012909:Snake Bites / Q000628:therapy*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000997:Antivenins; C431183:Crotalidae Polyvalent immune Fab; D007140:Immunoglobulin Fab Fragments
keywords: Agkistrodon; Equipoise; US Food and Drug Administration; antivenom; clinical trials; copperhead; ethics; placebo-controlled; snakebite