CLINICAL TRIALS
Ethics
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 2014, Vol. 11(5) 560–564 Ó The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1740774514543538 ctj.sagepub.com
Charles J Gerardo1, Eric J Lavonas2,3 and Ross E McKinney4
Abstract Background: In 2000, the US Food and Drug Administration approved CroFabÒ 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. Keywords Equipoise, ethics, placebo-controlled, clinical trials, US Food and Drug Administration, copperhead, Agkistrodon, snakebite, antivenom
Background 1
In 2000, the US Food and Drug Administration (FDA) approved CroFabÒ Crotalidae Polyvalent Immune Fab, ovine (FabAV), for use in patients with minimal to moderate North American crotaline envenomations. The label includes indication for the management of patients with minimal or moderate North American Crotalid (Crotaline) envenomation. In addition to rattlesnakes (genus Crotalus), pygmy rattlesnakes (Sistrurus), and cottonmouth (Agkistrodon piscivorus), the crotaline sub-family includes copperhead snakes (Agkistrodon contortrix). In the United States, FabAV is the only commercially available
Division of Emergency Medicine, Department of Surgery, Duke University, Durham, NC, USA 2 Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, CO, USA 3 Division of Medical Toxicology, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA 4 Trent Center for Bioethics, Humanities, & History of Medicine, Duke University Medical Center, Department of Pediatrics, Duke University, Durham, NC, USA Corresponding author: Charles J Gerardo, Division of Emergency Medicine, Department of Surgery, Duke University, DUMC 3096, 2301 Erwin Rd, Durham, NC 27710, USA. Email: [email protected]
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antivenom for treatment of patients with crotaline envenomation, regardless of species.1 Although approved for all of these envenomations, FabAV is much less commonly used in copperhead as compared to rattlesnake envenomation.2 Due to the limitation of the currently available evidence regarding treatment, there is wide practice variation throughout the United States.3,4 Both conservative and more liberal use of FabAV is considered acceptable at present. In order to provide more definitive clinical evidence for the role of FabAV use in copperhead envenomation, a randomized, placebo-controlled trial (RCT) of FabAV specifically for copperhead bites was initiated in 2013.5,6 Although trials of approved drugs for new indications are common, an RCT with a placebo comparator for an approved indication 13 years after approval is rare.7 This unique situation has raised ethical concerns regarding the use of placebo in copperhead envenomation. In fact, during site feasibility assessments, some of the potential research sites refused to participate on ethical grounds. This provides an opportunity to discuss the principles and methods that can be employed to mitigate any potential ethical issues in a study of this nature.
Orphan drug designation through approval and the need for a RCT In order to promote drug development for rare disease, the US Congress passed the Orphan Drug Act of 1983. The underlying ethical principle of this policy is to facilitate access to treatment for patients, regardless of the prevalence of their disease.8 As there are fewer than 9000 crotaline envenomations in the United States per year, this condition satisfies the definition of ‘‘rare disease.’’9,10 During its development in 1994, FabAV received orphan drug designation from the FDA. The benefits of orphan drug designation are designed to provide incentive to pharmaceutical companies for drug development in the form of grants to perform clinical trials, tax incentives, and extended exclusivity. Additionally, the FDA will work with the pharmaceutical company by providing regulatory advice on protocol design.10 This is intended to ensure focused and efficient clinical trials, as enrollment can be difficult. As of 2012, approximately 400 orphan drugs have been approved. Yet the clinical trials leading to approval for orphan drugs have revealed substantial differences in size, blinding, use of a control arm, randomization, and the use of surrogate end points for efficacy as compared with non-orphan drugs.11,12 The safety and efficacy of some of these drugs have subsequently been questioned. In fact, previously approved orphan drugs have been reconsidered after additional evidence has revealed either lack of effectiveness, increased harms, or lack of evidence justifying the extremely high cost.13,14 Currently, a variety of post-marketing evaluation techniques, including trials, are recommended but not universally required.15
During the development of FabAV, two registration clinical trials were performed that enrolled a total of 42 patients.16,17 Neither trial included a placebo or nonFabAV comparator arm. In addition to their small size and lack of comparator, these trials contained important limitations to the subsequent use of FabAV in the treatment of copperhead envenomation. Copperhead envenomation syndromes tend to be milder than other crotaline envenomation syndromes. For example, rattlesnake envenomation has been associated with death, significant coagulopathy, serious systemic symptoms such as renal failure, and severe local tissue manifestations such as rhabdomyolysis and tissue loss.18–20 Death, significant morbidity, bleeding, or clinically important coagulopathy in copperhead envenomation is exceedingly rare.3,21–24 The primary clinical outcomes of importance in copperhead envenomation are local tissue injury and impaired limb function. Despite rare prolonged disability, this injury is typically self-limited, and the majority of patients have full recovery within 2–4 weeks.25,26 Secondary to this more benign clinical course and the significant adverse reaction profile of the existing (equine) antivenom at the time these trials were conducted, fewer than 5% of copperhead envenomation patients were treated with antivenom. The majority of these patients were treated with supportive care only without any specific venom-directed therapy. Investigators believed it was unethical to expose these patients to an antivenom product that at the time was experimental, and patients with copperhead envenomation were excluded from the trials (R.C. Dart, personal communication with E.J. Lavonas, 2012).21 In addition to excluding this subgroup, both trials lacked important clinical outcome measures relevant to copperhead envenomation. The primary outcomes in the two clinical trials of FabAV were the snakebite severity score (SSS) and an unstructured assessment of clinical response by the treating physician/investigator. The SSS assesses local tissue symptoms, including the extent of limb pain, swelling, and ecchymosis.27 However, limb function and/or the resolution of disability was not assessed, and efficacy did not extend past hospital discharge. As these important outcomes were not obtained, there are no available outcome measures regarding limb recovery in rattlesnake envenomation that can be extrapolated to copperhead envenomation. The FDA approval of FabAV was based on efficacy and safety data obtained from rattlesnake envenomations; yet the approved label broadly indicated treatment for all North American crotaline envenomations. In this case, the registration process did not truly meet the evidentiary burden to support a consistent rationale for use of FabAV in copperhead envenomation. More data are needed to better align good clinical practice with more definitive evidence and are consistent with previous recommendations for post-marketing clinical studies of orphan drugs.28
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Ethical framework of proposed study There are a number of published guidelines that can be used to address the ethical concerns involved in designing a placebo-controlled clinical trial for the treatment of a disease, in this case, copperhead envenomation, when an FDA-approved drug is available. Ethical guidelines governing clinical trial design and conduct began with the adoption of the Nuremberg Code and Declaration of Helsinki and have been refined through work such as the Belmont Report and the World Health Organization: Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products. In 2000, the basic philosophy and principles of these guidelines were consolidated into a single framework consisting of seven requirements for ethical research: clinical value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for enrolled subjects.29 The requirements for clinical value, scientific validity, and a favorable risk–benefit ratio are of particular importance in the current copperhead RCT.
Clinical equipoise: validity and value In order for a clinical trial to be ethical, there typically is legitimate clinical equipoise regarding the therapy, and this controversy should exist at the level of the scientific community.30–32 The existing clinical equipoise in support of this clinical trial is best described by further detailing the lack of knowledge on FabAV use in copperhead envenomation and subsequent variation in treatment recommendations and present clinical practice. In addition to the issues with the registration clinical trials, a review of the published literature base for FabAV in copperhead envenomation reveals a paucity of observational evidence accrued since approval. A retrospective chart review done in 2004 showed progression of local tissue effects stopped in 88% of 32 FabAV-treated patients sustaining copperhead envenomation.22 These treated patients comprised only 8% of the available copperhead envenomations, and the untreated patient charts were not reviewed. As this study evaluated acute local symptoms only, the importance of these symptoms in determining longer term limb function has been questioned. An editorial accompanying this report stated, the routine use of [CroFabÒ] in the patient with mild to moderate local swelling alone should be based on evidence of improved outcomes, not just the likelihood of less swelling. In addition, it is important that any potential benefit be determined in a prospective, controlled manner to obtain the best evidence for cost-effective treatment of these patients.33
In this trial, the use of a previously validated patientreported outcome that has been evaluated specifically in copperhead envenomation addresses this concern.26
Due to the limitations of the existing evidence, medical experts have made broad treatment recommendations. Many experts recommend the on-label use of FabAV in all crotaline envenomations based on clinical presentation, regardless of snake species; others advocate categorically withholding FabAV from copperhead envenomation victims and providing supportive care only.4,34–36 These disparate practice recommendations have led to wide variation in antivenom use. The reported proportion of copperhead envenomation patients treated with FabAV ranges from 0% at some centers to 90% at others.4,5 The protocol steering committee for this study contained four physicians experienced in the management of copperhead envenomation. Two of these investigators use FabAV infrequently, whereas two use it for the majority of copperhead envenomations. Appointing protocol steering committee members who represent the diverse practice patterns ensures that a wide variety of clinician viewpoints are addressed through study design. Resolution of this clear existing clinical equipoise will provide clinical value to society. The Belmont Report specifically states that research ‘‘makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer inspection turn out to be dangerous.’’37 If this trial demonstrates FabAV is ineffective in copperhead envenomation, we can both recommend and research alternative interventions in an effort to develop a more effective therapeutic approach. If it demonstrates effectiveness, we can ensure that a greater proportion of patients who could benefit from the therapy receive it. As society stands to benefit from the results of this trial, whether or not the therapy is effective, it meets the ethical precondition of clinical value.
Favorable risk–benefit ratio The aforementioned guidelines reinforce the ethical requirement for a favorable risk–benefit ratio when considering placebo-controlled clinical trial design. The risks to the patients must be minimized, and the net risks, if any, must not be excessive; the potential benefits are enhanced, and the potential value to the patient and society is proportionate to the risks.29,38,39 In the current trial, the potential net risks to the enrolled patient will depend on whether the therapy provides clinical benefit or not and there is no a priori reason to assume that increased net risks exist in either arm. If FabAV is effective in mild or moderate copperhead envenomation, there are potentially worse outcomes for placebo arm patients. This risk to the individual patient is minimized by offering rescue therapy in the event they progress to a severe envenomation syndrome. Rescue therapy for disease progression to a point where there is no longer uncertainty of treatment benefit is consistent with published recommendations.38,39 Additionally, overall risks of the trial are
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minimized by the inclusion of an interim analysis that has stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial. In this scenario, the number of patients exposed to placebo will be minimized if clear efficacy is demonstrated. On the contrary, if FabAV is ineffective or only marginally beneficial for this indication, the primary risk is from adverse reactions to a drug with minimal potential benefit. Based on our current understanding of this medication, the risks from FabAV itself are limited. The risk of immediate hypersensitivity reaction is 8%, and serum sickness is 13%.40 In the case of immediate hypersensitivity, most events are mild with approximately 1.6% being severe, and most of these patients do well after receiving antihistamines, corticosteroids, and by slowing or completely stopping the FabAV.41 FabAV appears to be well tolerated, with a much better adverse effect profile in comparison with most antivenoms.42 This study has minimal incremental risk for participants and is justified by its value.
Conclusion The current placebo-controlled RCT of FabAV in copperhead envenomation is necessary to adequately resolve the current clinical equipoise surrounding treatment of this rare but potentially serious condition. The design and planned conduct of this clinical trial meets the requirements of value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for enrolled subjects, necessary for ethical clinical research. Although a post-market clinical study of this nature is unusual when an approved indication exists, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects. Acknowledgements We would like to thank Thomas King, MPH, for his review of this article.
Declaration of conflicting interests Charles J Gerardo, MD, MHS receives research funding from BTG International, Inc. Eric J Lavonas, MD is employed by Denver Health and Hospital Authority which has research, consulting, and call center agreements with BTG International, Inc. and the manufacturer of competing antivenom products. Dr. Lavonas has received research through his employer from BTG International, Inc. Dr. Lavonas has provided expert testimony related to snake envenomation; all compensation for these services is accrued to Denver Health Foundation.
Funding This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. BTG International, Inc. CroFabÒ (Crotalidae Polyvalent Immune Fab (Ovine)) (package insert). West Conshohocken, PA: BTG International, Inc., 2012; http:// www.crofab.com/documents/CroFab-Prescribing_Information.pdf (2013, accessed 12 February 2014). 2. Spiller HA, Bosse GM and Ryan ML. Use of antivenom for snakebites reported to United States poison centers. Am J Emerg Med 2010; 28(7): 780–785. 3. Evans C, Drake WG, Diskina M, et al. Hematologic abnormalities and bleeding in copperhead snakebite. Wilderness Environ Med 2014; 25: 116. 4. Walker JP and Morrison RL. Current management of copperhead snakebite. J Am Coll Surg 2011; 212(4): 470–474. 5. BTG International, Inc. A randomized, double-blind, placebo-controlled study comparing CroFabÒ versus placebo with rescue treatment for copperhead snake envenomation (Copperhead RCT) [NCT01864200], http:// clinicaltrials.gov/show/NCT01864200 6. Guyatt GH, Haynes RB, Jaeschke RZ, et al. Users’ Guides to the Medical Literature: XXV. Evidence-based medicine: principles for applying the Users’ Guides to patient care. Evidence-Based Medicine Working Group. JAMA 2000; 284(10): 1290–1296. 7. Friedman LM, Furberg CD and DeMets DL. Fundamentals of clinical trials. 4th ed. New York: Springer, 2010, p. 11. 8. Cote A and Keating B. What is wrong with orphan drug policies? Value Health 2012; 15(8): 1185–1191. 9. O’Neil ME, Mack KA and Gilchrist J. Epidemiology of non-canine bite and sting injuries treated in U.S. emergency departments, 2001–2004. Public Health Rep 2007; 122(6): 764–775. 10. Department of Health and Human Services. The Orphan Drug Act—implementation and impact. May 2001. The Office of the Inspector, General, http://oig.hhs.gov/oei/ reports/oei-09-00-00380.pdf 11. Mitsumoto J, Dorsey ER, Beck CA, et al. Pivotal studies of orphan drugs approved for neurological diseases. Ann Neurol 2009; 66(2): 184–190. 12. Kesselheim AS, Myers JA and Avorn J. Characteristics of clinical trials to support approval of orphan vs. nonorphan drugs for cancer. JAMA 2011; 35(22): 2320–2326. 13. US Food and Drug Administration. Mylotarg (gemtuzumab ozogamicin): market withdrawal. 21 June 2010, http://www.fda.gov/safety/medwatch/safetyinformation/ safetyalertsforhumanmedicalproducts/ucm216458.htm (accessed 18 April 2014). 14. Hirschler BUK says Novartis, Bristol cancer drug too costly. February 2010, http://www.reuters.com/article/ 2010/02/09/britain-cancer-idUSLDE61718V20100209 (accessed 18 April 2014). 15. Kesselheim AS and Gagne JJ.Strategies for postmarketing surveillance of drugs for rare diseases. Clin Pharmacol Ther 2014; 95(3): 265–268. 16. Dart RC, Seifert SA, Carroll L, et al. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med 1997; 30(1): 33–39. 17. Dart RC, Seifert SA, Boyer LV, et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine)
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Clinical Trials 11(5) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med 2001; 161(16): 2030–2036. Yin S, Kokko J, Lavonas E, et al. Factors associated with difficulty achieving initial control with crotalidae polyvalent immune fab antivenom in snakebite patients. Acad Emerg Med 2011; 18(1): 46–52. Bush SP and Jansen PW.Severe rattlesnake envenomation with anaphylaxis and rhabdomyolysis. Ann Emerg Med 1995; 25(6): 845–848. Bush SP, Wu VH and Corbett SW.Rattlesnake venominduced thrombocytopenia response to Antivenin (Crotalidae) Polyvalent: a case series. Acad Emerg Med 2000; 7(2): 181–185. Thorson A, Lavonas EJ, Rouse AM, et al. Copperhead envenomations in the Carolinas. J Toxicol Clin Toxicol 2003; 41(1): 29–35. Lavonas EJ, Gerardo CJ, O’Malley G, et al. Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment of copperhead snakebite. Ann Emerg Med 2004; 43(2): 200–206. Chuang R, Kokko J, Mlynarcheck SL, et al. Rattlesnake versus Agkistrodon envenomations: venom effects differences. J Med Toxicol 2010; 6(2): 240–241. Bowers R, Kwinter D, Shaw C, et al. The utility of serial coagulation profiles in the management of Agkistrodon contortrix envenomation. Ann Emerg Med 2012; 60(4): S124. Lavonas EJ, Kerns WP, Gerardo CJ, et al. Long-term limb function outcomes after copperhead snakebite. Ann Emerg Med 2008; 52(4): S141–S142. Lavonas E, Spradley EA, Gillman SM, et al. Signs, symptoms, and functional impairment during recovery from copperhead snakebite. J Med Toxicol 2013; 9: 83. Dart RC, Hurlbut KM and Garcia R. Validation of a severity score for the assessment of crotalid snakebite. Ann Emerg Med 1996; 27(3): 321–326. Dupont A and Van Wilder PB. Access to orphan drugs despite poor quality of clinical evidence. Br J Clin Pharmacol 2011; 71(4): 488–496. Emanuel EJ, Wendler D and Grady C. What makes clinical research ethical? JAMA 2000; 283(20): 2701–2711. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141–145. Fried C. Medical experimentation: personal integrity and social policy. Amsterdam: North-Holland Publishing, 1974.
32. Miller P and Weijer C. Rehabilitating equipoise. Kennedy Inst Ethics J 2003; 13(2): 93–118. 33. Caravati EM. Copperhead bites and Crotalidae polyvalent immune Fab (ovine): routine use requires evidence of improved outcomes. Ann Emerg Med 2004; 43(2): 207–208. 34. Weant KA, Bowers RC, Reed J, et al. Safety and costeffectiveness of a clinical protocol implemented to standardize the use of Crotalidae polyvalent immune Fab antivenom at an academic medical center. Pharmacotherapy 2012; 32(5): 433–440. 35. Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med 2011; 11: 2. 36. Corneille MG, Larson S, Stewart RM, et al. A large single-center experience with treatment of patients with crotalid envenomations: outcomes with and evolution of antivenin therapy. Am J Surg 2006; 192(6): 848–852. 37. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Ethical principles and guidelines for the protection of human subjects of research (Office of the Secretary). April 1979. Department of Health, Education, and Welfare, http:// www.hhs.gov/ohrp/humansubjects/guidance/belmont.html 38. Holubkov R, Dean JM, Berger J, et al. Is ‘‘rescue’’ therapy ethical in randomized controlled trials? Pediatr Crit Care Med 2009; 10(4): 431–438. 39. Morris AD, Zaritsky AL and LeFever G.Evaluation of ethical conflicts associated with randomized, controlled trials in critically ill children. Crit Care Med 2000; 28(4): 1152–1156. 40. Schaeffer TH, Khatri V, Reifler LM, et al. Incidence of immediate hypersensitivity reaction and serum sickness following administration of Crotalidae polyvalent immune Fab antivenom: a meta-analysis. Acad Emerg Med 2012; 19(2): 121–131. 41. Lavonas EJ, Kokko J, Schaeffer TH, et al. Short-term outcomes after Fab antivenom therapy for severe crotaline snakebite. Ann Emerg Med 2011; 57(2): 128–137.e3. 42. Leon G, Herrera M, Segura A, et al. Pathogenic mechanisms underlying adverse reactions induced by intravenous administration of snake antivenoms. Toxicon 2013; 76: 63–76.
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Ethics
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 2014, Vol. 11(5) 560–564 Ó The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1740774514543538 ctj.sagepub.com
Charles J Gerardo1, Eric J Lavonas2,3 and Ross E McKinney4
Abstract Background: In 2000, the US Food and Drug Administration approved CroFabÒ 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. Keywords Equipoise, ethics, placebo-controlled, clinical trials, US Food and Drug Administration, copperhead, Agkistrodon, snakebite, antivenom
Background 1
In 2000, the US Food and Drug Administration (FDA) approved CroFabÒ Crotalidae Polyvalent Immune Fab, ovine (FabAV), for use in patients with minimal to moderate North American crotaline envenomations. The label includes indication for the management of patients with minimal or moderate North American Crotalid (Crotaline) envenomation. In addition to rattlesnakes (genus Crotalus), pygmy rattlesnakes (Sistrurus), and cottonmouth (Agkistrodon piscivorus), the crotaline sub-family includes copperhead snakes (Agkistrodon contortrix). In the United States, FabAV is the only commercially available
Division of Emergency Medicine, Department of Surgery, Duke University, Durham, NC, USA 2 Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, CO, USA 3 Division of Medical Toxicology, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA 4 Trent Center for Bioethics, Humanities, & History of Medicine, Duke University Medical Center, Department of Pediatrics, Duke University, Durham, NC, USA Corresponding author: Charles J Gerardo, Division of Emergency Medicine, Department of Surgery, Duke University, DUMC 3096, 2301 Erwin Rd, Durham, NC 27710, USA. Email: [email protected]
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antivenom for treatment of patients with crotaline envenomation, regardless of species.1 Although approved for all of these envenomations, FabAV is much less commonly used in copperhead as compared to rattlesnake envenomation.2 Due to the limitation of the currently available evidence regarding treatment, there is wide practice variation throughout the United States.3,4 Both conservative and more liberal use of FabAV is considered acceptable at present. In order to provide more definitive clinical evidence for the role of FabAV use in copperhead envenomation, a randomized, placebo-controlled trial (RCT) of FabAV specifically for copperhead bites was initiated in 2013.5,6 Although trials of approved drugs for new indications are common, an RCT with a placebo comparator for an approved indication 13 years after approval is rare.7 This unique situation has raised ethical concerns regarding the use of placebo in copperhead envenomation. In fact, during site feasibility assessments, some of the potential research sites refused to participate on ethical grounds. This provides an opportunity to discuss the principles and methods that can be employed to mitigate any potential ethical issues in a study of this nature.
Orphan drug designation through approval and the need for a RCT In order to promote drug development for rare disease, the US Congress passed the Orphan Drug Act of 1983. The underlying ethical principle of this policy is to facilitate access to treatment for patients, regardless of the prevalence of their disease.8 As there are fewer than 9000 crotaline envenomations in the United States per year, this condition satisfies the definition of ‘‘rare disease.’’9,10 During its development in 1994, FabAV received orphan drug designation from the FDA. The benefits of orphan drug designation are designed to provide incentive to pharmaceutical companies for drug development in the form of grants to perform clinical trials, tax incentives, and extended exclusivity. Additionally, the FDA will work with the pharmaceutical company by providing regulatory advice on protocol design.10 This is intended to ensure focused and efficient clinical trials, as enrollment can be difficult. As of 2012, approximately 400 orphan drugs have been approved. Yet the clinical trials leading to approval for orphan drugs have revealed substantial differences in size, blinding, use of a control arm, randomization, and the use of surrogate end points for efficacy as compared with non-orphan drugs.11,12 The safety and efficacy of some of these drugs have subsequently been questioned. In fact, previously approved orphan drugs have been reconsidered after additional evidence has revealed either lack of effectiveness, increased harms, or lack of evidence justifying the extremely high cost.13,14 Currently, a variety of post-marketing evaluation techniques, including trials, are recommended but not universally required.15
During the development of FabAV, two registration clinical trials were performed that enrolled a total of 42 patients.16,17 Neither trial included a placebo or nonFabAV comparator arm. In addition to their small size and lack of comparator, these trials contained important limitations to the subsequent use of FabAV in the treatment of copperhead envenomation. Copperhead envenomation syndromes tend to be milder than other crotaline envenomation syndromes. For example, rattlesnake envenomation has been associated with death, significant coagulopathy, serious systemic symptoms such as renal failure, and severe local tissue manifestations such as rhabdomyolysis and tissue loss.18–20 Death, significant morbidity, bleeding, or clinically important coagulopathy in copperhead envenomation is exceedingly rare.3,21–24 The primary clinical outcomes of importance in copperhead envenomation are local tissue injury and impaired limb function. Despite rare prolonged disability, this injury is typically self-limited, and the majority of patients have full recovery within 2–4 weeks.25,26 Secondary to this more benign clinical course and the significant adverse reaction profile of the existing (equine) antivenom at the time these trials were conducted, fewer than 5% of copperhead envenomation patients were treated with antivenom. The majority of these patients were treated with supportive care only without any specific venom-directed therapy. Investigators believed it was unethical to expose these patients to an antivenom product that at the time was experimental, and patients with copperhead envenomation were excluded from the trials (R.C. Dart, personal communication with E.J. Lavonas, 2012).21 In addition to excluding this subgroup, both trials lacked important clinical outcome measures relevant to copperhead envenomation. The primary outcomes in the two clinical trials of FabAV were the snakebite severity score (SSS) and an unstructured assessment of clinical response by the treating physician/investigator. The SSS assesses local tissue symptoms, including the extent of limb pain, swelling, and ecchymosis.27 However, limb function and/or the resolution of disability was not assessed, and efficacy did not extend past hospital discharge. As these important outcomes were not obtained, there are no available outcome measures regarding limb recovery in rattlesnake envenomation that can be extrapolated to copperhead envenomation. The FDA approval of FabAV was based on efficacy and safety data obtained from rattlesnake envenomations; yet the approved label broadly indicated treatment for all North American crotaline envenomations. In this case, the registration process did not truly meet the evidentiary burden to support a consistent rationale for use of FabAV in copperhead envenomation. More data are needed to better align good clinical practice with more definitive evidence and are consistent with previous recommendations for post-marketing clinical studies of orphan drugs.28
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Ethical framework of proposed study There are a number of published guidelines that can be used to address the ethical concerns involved in designing a placebo-controlled clinical trial for the treatment of a disease, in this case, copperhead envenomation, when an FDA-approved drug is available. Ethical guidelines governing clinical trial design and conduct began with the adoption of the Nuremberg Code and Declaration of Helsinki and have been refined through work such as the Belmont Report and the World Health Organization: Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products. In 2000, the basic philosophy and principles of these guidelines were consolidated into a single framework consisting of seven requirements for ethical research: clinical value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for enrolled subjects.29 The requirements for clinical value, scientific validity, and a favorable risk–benefit ratio are of particular importance in the current copperhead RCT.
Clinical equipoise: validity and value In order for a clinical trial to be ethical, there typically is legitimate clinical equipoise regarding the therapy, and this controversy should exist at the level of the scientific community.30–32 The existing clinical equipoise in support of this clinical trial is best described by further detailing the lack of knowledge on FabAV use in copperhead envenomation and subsequent variation in treatment recommendations and present clinical practice. In addition to the issues with the registration clinical trials, a review of the published literature base for FabAV in copperhead envenomation reveals a paucity of observational evidence accrued since approval. A retrospective chart review done in 2004 showed progression of local tissue effects stopped in 88% of 32 FabAV-treated patients sustaining copperhead envenomation.22 These treated patients comprised only 8% of the available copperhead envenomations, and the untreated patient charts were not reviewed. As this study evaluated acute local symptoms only, the importance of these symptoms in determining longer term limb function has been questioned. An editorial accompanying this report stated, the routine use of [CroFabÒ] in the patient with mild to moderate local swelling alone should be based on evidence of improved outcomes, not just the likelihood of less swelling. In addition, it is important that any potential benefit be determined in a prospective, controlled manner to obtain the best evidence for cost-effective treatment of these patients.33
In this trial, the use of a previously validated patientreported outcome that has been evaluated specifically in copperhead envenomation addresses this concern.26
Due to the limitations of the existing evidence, medical experts have made broad treatment recommendations. Many experts recommend the on-label use of FabAV in all crotaline envenomations based on clinical presentation, regardless of snake species; others advocate categorically withholding FabAV from copperhead envenomation victims and providing supportive care only.4,34–36 These disparate practice recommendations have led to wide variation in antivenom use. The reported proportion of copperhead envenomation patients treated with FabAV ranges from 0% at some centers to 90% at others.4,5 The protocol steering committee for this study contained four physicians experienced in the management of copperhead envenomation. Two of these investigators use FabAV infrequently, whereas two use it for the majority of copperhead envenomations. Appointing protocol steering committee members who represent the diverse practice patterns ensures that a wide variety of clinician viewpoints are addressed through study design. Resolution of this clear existing clinical equipoise will provide clinical value to society. The Belmont Report specifically states that research ‘‘makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer inspection turn out to be dangerous.’’37 If this trial demonstrates FabAV is ineffective in copperhead envenomation, we can both recommend and research alternative interventions in an effort to develop a more effective therapeutic approach. If it demonstrates effectiveness, we can ensure that a greater proportion of patients who could benefit from the therapy receive it. As society stands to benefit from the results of this trial, whether or not the therapy is effective, it meets the ethical precondition of clinical value.
Favorable risk–benefit ratio The aforementioned guidelines reinforce the ethical requirement for a favorable risk–benefit ratio when considering placebo-controlled clinical trial design. The risks to the patients must be minimized, and the net risks, if any, must not be excessive; the potential benefits are enhanced, and the potential value to the patient and society is proportionate to the risks.29,38,39 In the current trial, the potential net risks to the enrolled patient will depend on whether the therapy provides clinical benefit or not and there is no a priori reason to assume that increased net risks exist in either arm. If FabAV is effective in mild or moderate copperhead envenomation, there are potentially worse outcomes for placebo arm patients. This risk to the individual patient is minimized by offering rescue therapy in the event they progress to a severe envenomation syndrome. Rescue therapy for disease progression to a point where there is no longer uncertainty of treatment benefit is consistent with published recommendations.38,39 Additionally, overall risks of the trial are
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minimized by the inclusion of an interim analysis that has stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial. In this scenario, the number of patients exposed to placebo will be minimized if clear efficacy is demonstrated. On the contrary, if FabAV is ineffective or only marginally beneficial for this indication, the primary risk is from adverse reactions to a drug with minimal potential benefit. Based on our current understanding of this medication, the risks from FabAV itself are limited. The risk of immediate hypersensitivity reaction is 8%, and serum sickness is 13%.40 In the case of immediate hypersensitivity, most events are mild with approximately 1.6% being severe, and most of these patients do well after receiving antihistamines, corticosteroids, and by slowing or completely stopping the FabAV.41 FabAV appears to be well tolerated, with a much better adverse effect profile in comparison with most antivenoms.42 This study has minimal incremental risk for participants and is justified by its value.
Conclusion The current placebo-controlled RCT of FabAV in copperhead envenomation is necessary to adequately resolve the current clinical equipoise surrounding treatment of this rare but potentially serious condition. The design and planned conduct of this clinical trial meets the requirements of value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for enrolled subjects, necessary for ethical clinical research. Although a post-market clinical study of this nature is unusual when an approved indication exists, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects. Acknowledgements We would like to thank Thomas King, MPH, for his review of this article.
Declaration of conflicting interests Charles J Gerardo, MD, MHS receives research funding from BTG International, Inc. Eric J Lavonas, MD is employed by Denver Health and Hospital Authority which has research, consulting, and call center agreements with BTG International, Inc. and the manufacturer of competing antivenom products. Dr. Lavonas has received research through his employer from BTG International, Inc. Dr. Lavonas has provided expert testimony related to snake envenomation; all compensation for these services is accrued to Denver Health Foundation.
Funding This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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