FDA Staff Grapples With Absent Clinical Efficacy Data for Nasal Epinephrine
A lack of clinical efficacy data on epinephrine nasal spray remained a chief concern for FDA reviewers as the agency considers approval of the first noninjectable product for treating allergic reactions, including anaphylaxis.
Approximately 1% of hospitalizations and 0.1% of emergency department admissions from anaphylaxis result in death, and while injectable epinephrine products are the life-saving, first-line treatment for these severe allergic reactions, they can be underused for multiple reasons that include a fear of a needle-containing device.
But “there is no regulatory precedent for approval of a noninjectable epinephrine product for treatment of anaphylaxis,” FDA staff wrote.
ARS Pharmaceuticals is seeking approval of its 2 mg nasal spray (ARS-1, also known as neffy), as a needle-less alternative to mainstream epinephrine injections for the emergency treatment of type I allergic reactions, including anaphylaxis, in adults and children weighing 30 kg (~66 lbs) or more.
To support clinical efficacy in its application, the sponsor has submitted pharmacokinetic (PK)/pharmacodynamic (PD) data comparing the nasal spray to currently approved forms of injectable epinephrine and data from human factors studies detailing user experience and potential user errors.
“Given that ARS-1 is proposed for emergency treatment and that clinical efficacy data are not available, we expect the available comparative PK/PD data to be robust to support approval, and that residual uncertainties regarding efficacy and safety are minimized,” wrote FDA reviewers. “We also expect that potential risks of treatment are adequately studied to factor into assessment of benefit-risk.”
PK parameter data after a single dose of the epinephrine nasal spray were supportive when compared with a single dose of either Adrenalin 0.3 mg or EpiPen 0.3 mg after 10 minutes.
But two potential concerns among the PK/PD data were highlighted by agency staff: a lower concentration of epinephrine in the first 10 minutes following a single-dose of the intransal product, and diminished PK/PD sustainability when nasal congestion was induced by allergens.
Along with those issues, the committee will address whether or not the data for the nasal spray support a favorable benefit-risk assessment for the proposed indication.
Safety data for ARS-1 involved 134 subjects who received at least one dose of the product across three pivotal trials. No deaths or serious adverse events (AEs) were reported, and local AEs were largely anticipated given the route of administration (nasal discomfort in 10%, rhinorrhea in 3%). Other AEs included those commonly reported with epinephrine injection as well (headache in 6%, dizziness in 3%, and nausea in 3%).
ARS Pharmaceuticals had first reached out to the FDA regarding ARS-1 development in 2018, citing a plan based on PK/PD and safety data; clinical efficacy trials were not included in the development program given the feasibility constraints of conducting such trials in anaphylaxis.
“While the Division recognized the challenges of conducting a clinical trial, it had concerns regarding the sufficiency of PK/PD data to support an anaphylaxis indication, and whether data from healthy volunteers would be similar in patients during an anaphylaxis episode,” wrote FDA staff.
“Ultimately, the Applicant and FDA designed a clinical pharmacology program that may provide scientific bridging/justification to establish efficacy and safety for ARS-1,” according to the briefing document. “Throughout the interactions with ARS, the Division noted areas of uncertainty with a PK/PD approach that would need discussion with an FDA [Advisory Committee] panel.”
It is worth noting that at the time the EpiPen was approved, 36 years ago, PK/PD data were not required as part of the FDA approval process, while other, recent versions of epinephrine injection products were approved based on already established efficacy, human factors assessments, and product-specific information.
While the FDA typically follows the advice of its advisory committees, it is not required to do so.
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