Food and Drug Administration Approval of Artesunate for Severe Malaria: Enough to Achieve Best Practice?

Abstract

Intravenous artesunate has been the global standard of care for severe malaria for over 2 decades. Yet, until recently, artesunate has only been available to patients through an expanded-access protocol from the Centers for Disease Control and Prevention. In May 2020, the Food and Drug Administration approved artesunate, allowing US hospitals to stock the drug and ensuring prompt treatment for this life-threatening infection. However, because of artesunate's high cost and the infrequency of severe malaria in the United States, hospitals may be reluctant to stock the drug. As US health systems weigh the decision to stock artesunate, we propose a hospital tier framework to inform this decision and support clinicians caring for patients who present with severe malaria.

Intravenous artesunate recently became commercially available in the US for the treatment of severe malaria. We propose a framework to inform hospitals on planning prompt diagnosis and treatment, including considerations for stocking artesunate.

(See the Major Article by Abanyie et al on pages e866–72.)

In May 2020, the Food and Drug Administration (FDA) approved intravenous artesunate for the treatment of severe malaria [1], a welcome development for a disease that can be rapidly fatal without prompt therapy, and previously lacked an FDA-approved treatment. The FDA approval and resulting commercial availability of artesunate represents a long-awaited milestone because it allows hospitals to stock the drug-of-choice for severe malaria and decrease the time to treatment for this life-threatening infection. However, artesunate's high launch price and small market will likely dissuade many hospitals in the United States from stocking this essential medication. As the Centers for Disease Control and Prevention (CDC) phases out its current Investigational New Drug (IND) protocol for artesunate in September 2022 [2], a framework is needed for US hospitals to inform the decision to stock artesunate and ensure best practices when caring for patients with severe malaria.

For nearly half a century, the US drug market for severe malaria has been characterized by limited commercial interest, resulting in the use of substandard drugs and an overreliance on the CDC to procure and deliver antimalarials to hospitalized patients. Beginning in 1979, the CDC Drug Service was the sole supplier of intravenous (IV) quinine in the United States, the worldwide standard for severe malaria treatment at the time [3]. In 1991, quinidine received FDA approval for severe malaria and replaced quinine as first-line therapy in the United States [3]. Quinidine remained the only FDA-approved drug for severe malaria for the next 30 years. Although quinidine was initially widely stocked—due to its primary use as an anti-arrhythmic agent—as other more effective and safe anti-arrhythmic agents became available, fewer hospitals stocked quinidine, culminating in its discontinuation in 2017 (existing supplies expired in 2019).

Meanwhile, randomized controlled trials proved artesunate to be more efficacious and safer than quinine derivatives, leading the World Health Organization to recommend artesunate as first-line treatment for severe malaria in 2006. Yet, despite unequivocal acceptance of artesunate as the international standard, artesunate remained commercially unavailable in the United States for over a decade, leaving Americans with suboptimal treatment and the CDC with an outsized role. Since 2007, the CDC Drug Service has sponsored an expanded access IND protocol for artesunate, supplying the drug under select circumstances through pre-positioned artesunate stocks at US airport quarantine stations [4]. This has resulted in an average delivery time of 7 hours (personal communication on 5/9/22 between JDA/WMS and the CDC). Although admirable, this time frame is inadequate considering that the mortality associated with severe malaria is highest within the first 24 hours and it does not meet the accepted 1-hour standard of care for antimicrobial administration in sepsis.

Artesunate's FDA approval represents a major step forward because it allows US hospitals, for the first time in nearly 2 decades, to stock the global standard of care. Yet, barriers remain. Amivas LLC, the private company that received FDA approval for artesunate, set the list price of artesunate at $4980 wholesale acquisition cost per vial, or over $30 000 per average treatment course [5]. Amivas has defended its launch price, citing the expense of supplying an ultra-orphan injectable drug that meets FDA standards, as well as high manufacturing, distribution, and vendor costs [6]. Although comparable to the cost of other orphan drugs in the United States [7], many hospitals will be hesitant to stock artesunate in the face of already strained hospital pharmacy budgets. In 2021, hospitals spent $39.6 billion on prescription drugs, an 8.4% increase from the prior year [8]. Another potential barrier is the risk that product goes unused and expires on the shelf. This is a real risk considering that approximately 300 cases of severe malaria occur per year and the shelf life of artesunate is 24 months [9]. Alleviating some of this concern is Amivas’ return-of-goods policy, offering an 80% credit to hospitals that restock expired artesunate [10].

The conundrum faced by hospitals—whether to stock a high-cost, low-volume drug that can be lifesaving if given promptly— is not unique to artesunate. Consider the US experience with antidotes, which share many of the same characteristics as artesunate. Responding to concerns about insufficient stocking, in 2018 an expert consensus panel developed guidelines for hospital stocking of antidotes that take into consideration the heterogenous settings in which hospitals provide emergency care [11]. Similarly, as health systems across the United States weigh the decision to stock artesunate, a framework is needed to inform this decision, systematically foreplan, and better equip clinicians caring for patients with severe malaria. Although it would be ideal for all hospitals to stock artesunate, this may not be feasible or practical. To promote prompt access for the greatest number of patients, we propose a framework that places hospitals into 1 of 3 tiers based on institutional capacity to diagnose and manage severe malaria (Figure 1).

Figure 1.

Hospital tier system for stocking artesunate. Abbreviations: ICU, intensive care unit; RDT, rapid malaria antigen testing. ¹Microscopy results available in <3 hours. ²Strongly encourage stocking a least 1 dose of intravenous artesunate in addition to stocking the oral antimalarial artemether-lumefantrine (Coartem). ³Stock an acceptable oral antimalarial treatment drug (eg, artemether-lumefantrine, atovproguanil, or quinine).

Most hospitals should have the capacity to quickly diagnose malaria using rapid malaria antigen testing (RDT) or have access to microscopy, which is the gold standard for diagnosing severe malaria. Hospitals with reliable in-house microscopy and intensive care unit (ICU) capacity are considered tier 1 and should stock artesunate because they are well equipped to both diagnose and manage critically ill patients with severe malaria, for whom serial microscopy to quantitate parasitemia is a necessary component of treatment.

Hospitals that have in-house RDT but delayed microscopy (eg, send-out) or lack ICU capacity are considered tier 2 hospitals. These hospitals are well positioned to initiate antimalarial therapy but may be unable to provide optimal ongoing care of critically ill patients with severe malaria. As such, these hospitals should strongly consider stocking at least 1 dose of artesunate for prompt administration prior to transfer to a tier 1 hospital. Additional motivation for stocking artesunate may arise from other institutional factors, such as a history of treating patients with severe malaria, serving populations who frequently travel to sub-Saharan Africa where Plasmodium falciparum is highly endemic (responsible for most cases of severe malaria), and a desire to provide equitable care. Tier 2 hospitals that choose not to stock artesunate should stock artemether-lumefantrine (Coartem, Novartis Pharmaceuticals), an oral agent used to treat uncomplicated malaria that is the preferred alternative option when artesunate is not immediately available [1].

Alternatively, tier 2 hospitals with ICU capacity may choose to continue managing patients with severe malaria, rather than transferring these patients to a tier 1 facility, if microscopy results can be obtained within a reasonable time frame to guide clinical management. If a hospital anticipates managing patients with severe malaria, they should stock at least 1 dose of artesunate in addition to artemether-lumefantrine. All hospitals should also have an institutional protocol in place to acquire artesunate within 8 hours from the distributor, accounting for anticipated delays (eg, requests occurring in the evening or weekends). If this process will take more than 8 hours, proactively identifying an alternative process for obtaining artesunate is needed, such as establishing a mechanism to purchase artesunate from a neighboring institution [2]. Pre-emptive information sharing and collaboration locally may assist hospitals to avoid process inefficiencies when obtaining artesunate and facilitate timely treatment [12].

Finally, hospitals without in-house RDT or prompt microscopy are considered tier 3. These hospitals will struggle to diagnose malaria quickly and should have a protocol in place for the management of febrile returning travelers for whom a high index of suspicion for severe malaria exists. An oral antimalarial agent should be stocked by tier 3 hospitals for immediate initiation when malaria is suspected, with prompt referral to a tier 1 or 2 hospital.

The commercial entry of artesunate in the United States represents necessary, but insufficient, progress in the treatment of severe malaria. Now steps are needed to ensure that the value of artesunate is realized and that health systems are empowered to deliver life-saving treatment without delay.

Notes

Acknowledgments. The authors thank Dr. Kathrine Tan (Centers for Disease Control and Prevention) for her thoughtful review of this manuscript.

Financial support. C. M. T. receives support from the National Institute of Allergy and Infectious Diseases (grant number T32 AI055433).