Ensuring the Efficacy and Safety of Approved Medications

In 2023, the U.S. Food and Drug Administration (FDA) reviewed applications for two intranasal products intended for use in the pre-hospital setting for potentially-life threatening conditions: epinephrine for anaphylaxis and nalmefene for reversal of opioid overdose. Because both products had been previously marketed in parenteral formulations, the sponsors used Abbreviated New Drug Applications (ANDA), which require bioequivalence data but not safety and efficacy studies. Approval of drugs in this manner relies on previously obtained safety and efficacy data [1]. While this may streamline the approval process, using an ANDA allowed the sponsors to bypass critical studies in the intended patient population and care setting, creating a situation that may ultimately result in patient harm.

The FDA reviewed an application for an intranasal epinephrine product (neffy™) as a needle-free alternative to intramuscular epinephrine for the treatment of allergic reactions and anaphylaxis [2]. The potential advantages of such a product are important, as a needle-free administration route should mitigate hesitancy to administer medication via injection, fear of needles in pediatric patients, and unintended discharge of the product into a digit. The manufacturer presented pharmacokinetic data comparing various intramuscular epinephrine products with the intranasal product. There was notable variability in the pharmacokinetics, with the intranasal product having lower plasma concentrations in the first several minutes after administration. These pharmacokinetic studies were conducted in healthy individuals and in a model using patients with allergic rhinitis to simulate conditions of anaphylaxis. The application relied heavily on pharmacodynamic data and surrogate markers of efficacy, stating it was not ethical or practical to conduct studies in patients with anaphylaxis [2, 3]. Furthermore, intranasal epinephrine was not studied in the community, despite its intended use in this setting. Although an advisory panel dividedly supported approval of intranasal epinephrine, the FDA declined to approve the product until more data were available [4].

Similarly, nalmefene nasal spray was recently reviewed and approved using an ANDA. Nalmefene is a long-acting opioid antagonist with a high affinity for the opioid receptor originally approved by the FDA for parenteral administration in 1995 [5]. In 2008, injectable nalmefene was withdrawn from the market by the manufacturer for business reasons, in part due to the large market share and favorable pharmacokinetics of the alternative opioid antagonist, naloxone. The ongoing opioid crisis and concern for opioid use in a terrorist act prompted renewed interest in nalmefene and on May 22, 2023, the FDA approved intranasal nalmefene (Opvee™) for the emergency treatment of known or suspected opioid overdose. The nasal spray formulation is intended to be used in the pre-hospital, healthcare, and community settings [6]. In addition, a parenteral form of nalmefene was also recently re-introduced by Purdue Pharma for use by healthcare providers; this was approved using an ANDA [7].

Because nalmefene had previously been approved by the FDA, the manufacturer was not required to present the FDA with safety and efficacy data for the intranasal route, but only to demonstrate bioequivalence of the new administration route with the previously approved injectable product [1]. While pharmacokinetic studies comparing intranasal to intramuscular nalmefene were favorable, the studies used to support its approval were conducted in healthy volunteers [8, 9]. Efficacy studies and safety assessments of intranasal nalmefene in the intended patient population - those with known or suspected opioid overdose - were neither required nor performed. The existing efficacy data for parenteral nalmefene are limited to small studies in the healthcare setting [10, 11]. There are no data on intranasal administration by bystanders or first responders in the community, one of the settings where the drug is intended to be utilized. Additionally, given high rates of opioid dependence in the intended patient population, studies should examine the potential safety issues associated with administration of a longer acting opioid antagonist (nalmefene versus naloxone) inducing prolonged precipitated withdrawal. This may be less of a problem in population with a low likelihood of opioid dependence, such a terrorist attack.

While both products may have merit, the approval process has some notable limitations - the lack of efficacy and safety studies in the intended patient population and administration setting. Both opioid overdose and anaphylaxis are potentially life-threatening conditions and administration of timely and effective treatment is critical. However, the pathophysiology of anaphylaxis is not the same as nasal rhinitis and a patient who is in cardiac arrest or in a peri-arrest state secondary to anaphylaxis is physiologically different than a healthy volunteer. Failure of intranasal epinephrine in the community setting can result in harm, as alternative treatments or resuscitative therapies may not be readily available to treat anaphylaxis. Likewise, if nalmefene were to fail in a healthcare setting, there would likely be access to ventilatory support and additional resuscitative measures. Furthermore, the prevalent opioid in the 1980’s when nalmefene was studied was heroin and prescription opioids, which are markedly pharmacologically distinct from fentanyl and similar analogues that we see today. With nalmefene’s long half-life, patients who are opioid dependent may experience precipitated withdrawal that can be prolonged and difficult to treat. Even without this adverse effect, nalmefene’s long half-life may lead to longer ED observation times awaiting its effects to wane to allow assessment for the persistence of opioid intoxication.

Sponsors justify the use of surrogate data by claiming that it is not ethical or feasible to conduct adequate safety and efficacy trials in the intended patient populations. We believe it is possible to conduct efficacy trials in patients in controlled settings, such as in the prehospital or emergency department (ED) settings, or in the case of epinephrine, an allergist’s office. In these settings, established treatments could be used if the investigational intranasal therapies failed. Informed consent is challenging, but various alternative consent strategies could be utilized including Emergency Research Consent Waivers. For anaphylaxis, where the intervention (epinephrine) is timely but occasionally predictable (such as with food challenges) patients could be preconsented; i.e., patients could give informed consent for a trial of intramuscular versus intranasal epinephrine in the event anaphylaxis were to occur. While this method of consent is not always successful and is complicated, it is feasible for some emergency conditions [12–14]. For less predictable conditions in which critical illness itself renders the patient unable to consent (such as severe anaphylactic shock or opioid overdose), randomized clinical trials are still possible in the U.S. In 1996, FDA finalized rules for Exception From Informed Consent (EFIC) requirements for emergency research (21 CFR 50.24) [15]. These regulations allow for a waiver of informed consent in both the out-of-hospital and hospital environments under the narrow circumstances when the condition of the patient and the necessary rapidity of the intervention make obtaining informed consent impracticable; patients with suspected opioid overdose requiring rescue with an antidote meet this definition. EFIC studies have numerous requirements, including community consultation, public disclosure before and after the trial, plans for contacting legally authorized representatives to seek consent, and formation of a data safety monitoring board. EFIC trials are also highly regulated; they require submission of an investigational new drug application with FDA. Though EFIC studies are time-consuming, expensive, and challenging, they may be conducted with federal oversight in a manner that still prioritizes patients’ welfare, safety, and rights. EFIC has been used to study numerous emergency conditions, including status epilepticus, traumatic brain injury, and cardiac arrest and may be a viable option for a trial comparing naloxone versus nalmefene in people with opioid overdose [16–20].

Perhaps, abbreviation of the drug approval process would be justified if these medications addressed an unmet need. However, there is no critical need for expedited approval of these drugs. Both of these new products address conditions that already have safe and effective therapies. Naloxone is an effective and affordable treatment for opioid overdose and has the advantage of not causing prolonged withdrawal. The higher mu-receptor affinity of nalmefene over naloxone, while factually correct, may be clinically irrelevant because both have greater affinity than that of fentanyl. Regardless, naloxone’s lower affinity may result in a smoother reversal of intoxication and, if concerns remain, is easily addressed through dose adjustment. We have decades of clinical experience using intramuscular epinephrine for anaphylaxis. While an effective needle-free epinephrine nasal spray does have significant advantages over injection, efficacy in the intended patient population and setting has not been established.

Intranasal epinephrine and nalmefene products may have merit and while there may be challenges in performing adequate studies, this can be accomplished. The failure of a rescue medication for a time-sensitive and life-threatening condition in the community would be disastrous. Additionally, prolonged precipitated withdrawal can cause harm to patients and may increase healthcare resource utilization. As medical toxicologists, with expertise in medication safety and adverse drug effects, we encourage more robust safety and efficacy data to avoid patient harm before these agents are available for widespread therapeutic use.

Funding

No funding was provided for this study.

Declarations

Financial Disclosures

The authors have no financial relationships relevant to this article to disclose.

Competing Interests

Drs. Nelson, Perrone, and Amirshahi have served on U.S. Food and Drug Advisory Panels.