Ethical considerations in design of a study to evaluate a US Food and Drug Administration–approved indication: Antivenom versus placebo for copperhead envenomation

Background

In 2000, the US Food and Drug Administration (FDA) approved CroFab^® 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 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 non-FabAV 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

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.

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.