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Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.
Clin Trials. 2014 Oct; 11(5):560-4.CT

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.

PURPOSE

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.

CONCLUSION

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+Show Affiliations

Division of Emergency Medicine, Department of Surgery, Duke University, Durham, NC, USA gerar001@mc.duke.edu.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.Trent Center for Bioethics, Humanities, & History of Medicine, Duke University Medical Center, Department of Pediatrics, Duke University, Durham, NC, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25055811

Citation

Gerardo, Charles J., et al. "Ethical Considerations in Design of a Study to Evaluate a US Food and Drug Administration-approved Indication: Antivenom Versus Placebo for Copperhead Envenomation." Clinical Trials (London, England), vol. 11, no. 5, 2014, pp. 560-4.
Gerardo CJ, Lavonas EJ, McKinney RE. Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation. Clin Trials. 2014;11(5):560-4.
Gerardo, C. J., Lavonas, E. J., & McKinney, R. E. (2014). Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation. Clinical Trials (London, England), 11(5), 560-4. https://doi.org/10.1177/1740774514543538
Gerardo CJ, Lavonas EJ, McKinney RE. Ethical Considerations in Design of a Study to Evaluate a US Food and Drug Administration-approved Indication: Antivenom Versus Placebo for Copperhead Envenomation. Clin Trials. 2014;11(5):560-4. PubMed PMID: 25055811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation. AU - Gerardo,Charles J, AU - Lavonas,Eric J, AU - McKinney,Ross E, Y1 - 2014/07/23/ PY - 2014/7/25/entrez PY - 2014/7/25/pubmed PY - 2015/7/15/medline KW - Agkistrodon KW - Equipoise KW - US Food and Drug Administration KW - antivenom KW - clinical trials KW - copperhead KW - ethics KW - placebo-controlled KW - snakebite SP - 560 EP - 4 JF - Clinical trials (London, England) JO - Clin Trials VL - 11 IS - 5 N2 - 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. PURPOSE: 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. CONCLUSION: 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. SN - 1740-7753 UR - https://www.unboundmedicine.com/medline/citation/25055811/Ethical_considerations_in_design_of_a_study_to_evaluate_a_US_Food_and_Drug_Administration_approved_indication:_antivenom_versus_placebo_for_copperhead_envenomation_ L2 - http://journals.sagepub.com/doi/full/10.1177/1740774514543538?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -