key: cord-0759177-yjct2pe3
authors: Lim, Sarah; DeBruin, Debra A.; Leider, Jonathon P.; Sederstrom, Nneka; Lynfield, Ruth; Baker, Jason V.; Kline, Susan; Kesler, Sarah; Rizza, Stacey; Wu, Joel; Sharp, Richard R.; Wolf, Susan M.
title: Developing an Ethics Framework for Allocating Remdesivir in the COVID-19 Pandemic
date: 2020-06-20
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.06.016
sha: b4de2c75baf269f8653ef5a4f571f4f209b2fe7d
doc_id: 759177
cord_uid: yjct2pe3

Abstract On May 1, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to allow use of the antiviral drug remdesivir to treat patients with severe COVID-19 disease. Remdesivir is an investigational drug studied in clinical trials for COVID-19 and is available to children and pregnant women through compassionate use access, but is not yet FDA-approved. In early May, the U.S. Department of Health and Human Services began to distribute remdesivir donated by Gilead Sciences, Inc., to hospitals and state health departments for emergency use; multiple shipments have since been distributed. This process has raised questions of how remdesivir should be allocated. The Minnesota Department of Health has collaborated with the Minnesota COVID Ethics Collaborative and multiple clinical experts to issue an “Ethical Framework for May 2020 Allocation of Remdesivir in the COVID-19 Pandemic.” The framework builds on extensive ethical guidance developed for public health emergencies in Minnesota prior to the COVID-19 crisis. The Minnesota remdesivir allocation framework specifies an ethical approach to distributing the drug (1) to facilities across the state, and then (2) among COVID-19 patients within each facility. This article describes the process of developing the framework and adjustments in the framework over time with emergence of new data, analyzes key issues addressed, and suggests next steps. Sharing this framework and the development process can encourage transparency and may be useful to other states formulating and refining their approach to remdesivir EUA allocation.

On May 1, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to allow use of the antiviral drug remdesivir to treat patients with severe COVID-19 disease. 1 That EUA was based on FDA "review of topline data" from two trials, one conducted by the National Institute of Allergy and Infectious Diseases (NIAID) 2 and the other sponsored by Gilead Sciences, Inc., the drug's manufacturer. 3 At the time the EUA was issued, neither trial's data had been published, although both have since been published in a peer-reviewed journal.

Remdesivir is an investigational drug being studied in clinical trials for COVID-19 4 and is available to children and pregnant women through compassionate use access, 5 but is not yet FDA-approved. In early May, the U.S. Department of Health & Human Services (HHS) began shipping supplies of remdesivir donated by Gilead to hospitals and state health departments for EUA distribution. 6 These shipments have raised urgent questions of how remdesivir should ethically be allocated. 7, 8 This article describes the process by which an ethics allocation framework was rapidly developed for the state of Minnesota to guide allocation. To develop this approach, the Minnesota Department of Health (MDH) collaborated with the Minnesota COVID Ethics Collaborative (MCEC) 9 and multiple clinical experts. The resulting "Ethical Framework for May 2020 Allocation of Remdesivir in the COVID-19 Pandemic" was first approved by the state's Commissioner of Health and subsequently amended in response to emerging data. 2 The amended framework dated May 24 appears in the Appendix. The document hosted on the MDH website will incorporate any subsequent amendments. 10 The remdesivir allocation framework presented here specifies an ethical approach to distributing the drug (1) to facilities across the state, and then (2) among COVID-19 patients within each facility. This article presents our approach to developing the guidance, identifies key issues and how we approached them, and suggests next steps.

The remdesivir framework is built on ethical guidance developed for public health emergencies in two prior projects: the Minnesota Pandemic Ethics Project (2007-10) 11 and Ethical Considerations for Crisis Standards of Care (2016) 12 and additionally draws on previous work by MCEC. 13 The prior guidance recommended that, in a public health emergency, an ethics support mechanism be deployed at the state level to share expertise rapidly and support ethical crisis response. 12, 14 In line with this guidance, the Minnesota COVID Ethics Collaborative (MCEC) was convened in March 2020 as a partnership between MDH, the State Health Care Coordination Center (SHCCC), Minnesota Hospital Association, and University of Minnesota (UMN). MCEC rapidly grew to more than 60 participants, including ethics and clinical experts from health systems across the state. To encourage open discussion, people participate not as representatives of their organizations but as individuals with subject matter expertise.

Shortly after receiving notification from HHS that Minnesota would be receiving shipments of remdesivir pursuant to the FDA's EUA, MDH reached out to MCEC on May 6 for ethics guidance on allocation. Because the first shipment was due imminently, MCEC quickly convened a multidisciplinary subgroup, including the co-leads, to work with MDH and clinical colleagues to develop an initial allocation framework. Those clinical colleagues included researchers leading clinical trials of remdesivir in Minnesota (J.V.B., S. Kline, S.R.).

The initial framework document was developed within days, before being reviewed by MDH and the Chair of its Science Advisory Team (SAT), approved by the Commissioner of Health, and disseminated across the state. After allocation of the initial shipment and clinical feedback, the full MCEC group met by videoconference to refine the framework. With publication of preliminary data from the NIAID trial on May 22, 2 the framework was amended. The Appendix presents the May 24 version of the framework. As of May 25, four shipments have been allocated using the remdesivir allocation framework, which is subject to further revision as new evidence emerges and the situation evolves.

Formulating an ethical framework for remdesivir allocation in May of 2020 posed significant challenges, including the scientific uncertainty surrounding the best use of remdesivir. 7 When the FDA issued its EUA on May 1 based on unpublished data from the NIAID and Gilead trials, the agency stated that (1) remdesivir was associated with a reduction in median time to recovery from 15 to 11 days in hospitalized patients with severe COVID-19, and (2) there was potential for a reduction in mortality from 11.6% to 8% that did not reach statistical significance. 15 However, preliminary results from the NIAID trial were not published until May 22, 2 more than two weeks after MDH had to make the first allocation, and results from the Gilead trial were not published until May 27. 3 This paucity of evidence when the initial ethical framework for EUA allocation was needed created uncertainty about which patient populations would benefit from remdesivir.

Moreover, although the EUA stated that eligible patients should have "severe" disease, the stated eligibility criteria were broad enough to encompass almost the entire clinical spectrum of inpatient respiratory disease. The EUA also stated that patients with "both suspected or laboratory confirmed COVID-19" may be considered for treatment, potentially broadening the pool of eligible patients even more. 1 The Minnesota allocation framework thus had to specify eligibility and prioritize patients for a limited resource in the face of uncertainty and an inadequate, though evolving, evidence base.

Faced with these uncertainties, we needed to develop "real-time" guidance that could be updated when new evidence and logistical realities emerged. The timeline from notice that Minnesota would receive an allocation to receipt of the first shipment was 4 days. We had to quickly formulate guidance that could be implemented across health care systems and facilities in Minnesota, and then be updated based on feedback concerning implementation, any new evidence that emerged, and the evolving shipment situation.

The Minnesota ethical framework for remdesivir allocation addresses four major issues: (A) guiding ethical values; (B) how to allocate remdesivir across facilities; (C) how to allocate remdesivir among patients within a facility; and (D) what processes facilities should use for allocation, documentation, and review. We present our approach below, with a text box highlighting key issues addressed more fully in the framework document reproduced in the Appendix.

What ethical values should guide allocation?

B. Responsibly allocate the scarce resource to reduce risk while providing benefit C. Save the most lives possible while respecting rights & fairness D. Promote the common good through transparency, accountability, and trustworthiness E. Use the best available evidence while addressing uncertainty

The remdesivir allocation framework is grounded in foundational ethical values identified in the prior ethics projects, 11,12,14,16 expressed as commitments to trustworthiness, public accountability, transparency, solidarity and mutual responsibility, respect for individuals and groups, fairness, and effectiveness and efficiency of response. To honor these fundamental commitments, crisis response must promote the public's health while respecting rights and ensuring fairness.

To achieve these objectives, Minnesota's remdesivir guidance prioritized those at greatest risk of mortality and serious morbidity, as well as those who stood to benefit from access to the drug. At each stage in developing the framework, we used the best available evidence and advice from clinical experts.

To ensure the framework protected the rights and interests of all, we adopted an approach that rejected allocation based on race, ethnicity, gender or gender identity, citizenship or immigration status, socioeconomic status, or ability to pay for treatment. The framework also disallowed allocation based on age, disability status, or comorbidities as criteria in and of themselves, unless directly relevant to clinical prognosis and likelihood of survival to hospital discharge.

In striving to meet the objective of protecting those at greatest risk while maximizing benefit of the resource, the framework allocates to patients based on need as well as likely benefit through survival to hospital discharge. In addition, the patient should not be imminently and irreversibly dying or terminally ill with life expectancy under 6 months (e.g., eligible for hospice). The framework focuses on short-term instead of longer-term prognosis (e.g., 1-year or 5-year survival) in order to avoid disadvantaging patients on the basis of age, comorbidities, and disabilities that are not germane to short-term survival. Focusing on short-term survival also avoids disadvantaging patients for systemic health inequities that may place them at risk for comorbidities and lower life expectancy.

Grounding remdesivir allocation in an explicit consideration of ethics contrasts with approaches that leave allocation to clinical discretion 17,18 without addressing the ethical values that should guide allocation. In Minnesota, the prior projects made it clear that allocation raises ethical questions that must be addressed. 11,12 Those projects involved extensive consultation with experts and the public. First, obtaining granular data on the number of clinically eligible patients per facility proved excessively burdensome, so we developed the closest practical proxy: the total number of COVID-positive patients in each facility, a number each facility was already reporting to MDH on a daily basis. For each remdesivir distribution, MDH asked the facility to subtract the number of patients in this group already on remdesivir (through compassionate use, clinical trials, or prior EUA allocations). Health care systems that included facilities outside of Minnesota were allocated remdesivir based on the patient census in their Minnesota facilities. However, the framework expressly allowed patients who transferred out of Minnesota facilities to take the remainder of their course with them, an important provision for rural patients who might need to transfer across a state border for more intensive care.

The framework's approach to allocation among facilities can be contrasted with reported approaches in other states, including those based on: physician request 19 ; random selection 20 among hospitals with COVID-positive patients; number of COVID patients and those "under investigation" in each hospital system 17 ; communities' COVID death rates 21 ; hospitalized COVID patients by county, and then distribute to acute care facilities within each county randomly or by a range of other methods 22 ; COVID patients in each facility's ICU over the last 14 days 23 ; hospitals reporting at least 10 COVIDpositive patients on ventilators or ECMO 24 ; percentage of mechanically ventilated patients 18 ; or total COVID patients and total COVID patients on ventilators in the last 7 days. 25 Allocating in Minnesota based on the number of COVID-positive patients minus those already on remdesivir offers more precision in approximating the number of eligible patients than many of these alternatives.

Allocation across facilities also required determining whether remdesivir would be distributed by assuming a 10-day course for each patient or a 5-day course. The FDA's EUA Fact Sheet for Healthcare Providers stated, "The optimal duration of treatment for COVID-19 is unknown." 15 It suggested that patients on invasive mechanical ventilation or ECMO receive a 10-day course, but other patients receive a 5-day course that could be extended to 10 days if they were not improving, based in part on data from Gilead's open-label trial which has now been published. 3 In order to allocate each shipment upon arrival and avoid a patient needing more medication after 5 days but being unable to get it, a 10-day course of medication was allocated for each patient. The framework instructed facilities to consider stopping remdesivir at 5 days in patients not on mechanical ventilation or ECMO, depending on the patient's clinical course, and then reallocating the available remdesivir to other patients.

How should remdesivir be allocated within a facility among patients?

• Clinical criteria for allocation are based on patient need (risk of serious morbidity to hospital discharge or mortality without the medication) and likelihood of benefit defined as recovery •

Highest priority: patients on advanced respiratory support (high-flow nasal cannula, CPAP, BiPAP) OR patients with three out of four characteristics: < 94% oxygen saturation on room air; respiratory rate > 30; lung infiltrates on imaging; using supplemental oxygen • Second priority: patients on who have been mechanically ventilated for < 5 days OR on ECMO for < 5 days •

When patients are otherwise of equal priority within a group and there is not sufficient drug for all patients in this group, a random process should be used to allocate • Patients who are imminently dying or terminally ill with life expectancy < 6 months should not be prioritized for access • Children and pregnant women are not included due to availability of remdesivir through the FDA's compassionate use program Developing recommendations for allocation of remdesivir among patients within a facility required determining how to meet the ethical objective of reducing risk of morbidity and mortality while maximizing likelihood that patients could benefit from the drug. However, the supply of medication was insufficient to treat all patients who fulfilled the broad eligibility criteria listed in the EUA and clinical trial data on which subgroups of patients might benefit most was not yet available. The Minnesota framework thus initially sought to meet the acute need of those patients who were the most severely ill -on mechanical ventilation, ECMO, or advanced respiratory support --and then sought to provide benefit to patients who were not yet as acutely ill, but had significant respiratory insufficiency.

This ethical prioritization led to the creation of a two-tier approach for remdesivir allocation. The guidance framework initially placed patients with COVID-19 pneumonia who were critically ill and receiving mechanical ventilation for ≤ 5 days, or on ECMO, or receiving advanced non-invasive respiratory support in the first priority tier. A 5-day cutoff for ventilation was chosen based on expert opinion from clinicians and remdesivir researchers that patients with more prolonged critical illness would be less likely to benefit from an antiviral drug. Patients were also required to meet the EUA's inclusion criteria based on kidney and liver function (GFR > 30ml/min, ALT < 5 times upper limit of normal). 15 The second priority tier included patients who did not meet tier-one criteria, but had severe disease and met three of four additional criteria for hypoxia and respiratory distress.

In drafting the initial framework, we debated whether the highest priority should be to treat patients earlier in their clinical course rather than patients already on mechanical ventilation or ECMO. However, without published data to resolve the question of which patients benefit from remdesivir, we relied on analysis of available sources 26-28 and clinical input to determine provisionally (1) which patients were most in need of remdesivir based on risk of serious morbidity and mortality without the medication, and (2) which patients were likely to benefit from access to remdesivir through recovery to hospital discharge.

After publication of preliminary data from the NIAID-funded trial of remdesivir on May 22, 2 we revised the framework's priorities. These data showed clearest benefit for hospitalized patients requiring supplemental oxygen, but not yet on advanced respiratory support, and possible benefit for those on advanced respiratory support. The preliminary data did not show benefit for those on mechanical ventilation or ECMO, although the sample size was small and the authors cautioned that "the follow-up time may have been too short to evaluate this subgroup." 2 Accordingly, we moved patients formerly in tier two to the highest priority tier and moved patients on mechanical ventilation and ECMO down to the second priority tier. Since the NIAID data suggested there may be benefit to patients on advanced respiratory support, these patients remained in tier one.

In making these changes, we demonstrated the flexibility of the Minnesota approach. The now-published NIAID trial data suggesting that earlier therapy is more beneficial are preliminary; further data may require further updates. The Minnesota framework was developed with a clear understanding of its provisional nature and the project team assumed that the evidence would continue to evolve.

In developing this allocation framework in the face of uncertainty, we debated using randomization more broadly. Instead of creating priority tiers, one could randomize all hospitalized patients with COVID-19 regardless of severity of illness. Alternatively, one could randomize across both the framework's tiers combined. However, the Minnesota framework is guided by the ethical objective to minimize risk and maximize benefit, insofar as it is possible to determine how to do so. The framework does recommend that when there is not enough remdesivir for patients within a given prioritization category, eligible patients should be randomized to ensure fairness.

The framework recognizes the importance of patient consent, given that remdesivir is an unapproved medication with the potential for serious adverse events. 2, 3, 15, 29 The framework recommends that patients be asked on admission whether they would be interested in receiving medications not yet approved but potentially available under an EUA. Broaching this issue early and distinguishing EUA access from compassionate use and clinical trials can facilitate decision making later in the patient's course. If a patient lacks decisional capacity or no substitute decision-maker is available, the framework recommends that clinicians allocate the remdesivir in keeping with the patient's best interests, unless the patient had previously declined EUA access. This avoids excluding patients simply because they are unbefriended (i.e., lacking a surrogate).

Ethical guidance developed in Minnesota's previous projects calls for prioritization of key workers to receive antiviral treatments. 16,p28-34 However, including priority for key workers would have been impossible to operationalize on the short timeline required for development and implementation of this framework, given complexities in defining the categories of key workers to be prioritized, identifying the relevant individuals within those categories, and ensuring the availability of this information to clinical teams for allocation decisions. In keeping with the evolving nature of the guidance and the flexibility of our approach, MCEC has begun discussions about how to incorporate appropriate priority for key workers in allocation frameworks moving forward.

What processes should facilities use for allocation, documentation, and review?

• Use a Triage Officer or Team (not bedside team) for randomization; facilities that have not yet deployed triage personnel may establish ad hoc triage processes • Remdesivir allocation should be documented at two levels: (a) patients who receive EUA remdesivir under this framework should have that documented in their electronic health record (EHR); and (b) facilities should maintain a log of allocation decisions (including randomization) to ensure transparency, accountability, and retrospective review

The remdesivir framework envisions that the bedside clinical care team will determine whether a patient meets the drug eligibility criteria specified in the guidance. However, if randomization is needed in either tier of patients because there are more eligible individuals than available courses, then the framework calls for a separation of roles. A Triage Officer or Team should perform randomization, instead of the clinicians providing care at the bedside. This separation preserves the integrity of the patient/provider relationship and so reduces potential moral distress and protects the fairness of the randomization process by minimizing bias. Indeed, the framework recommends that, insofar as possible, the Triage Officer or Team should not be provided with patient characteristics that are impermissible to consider in allocation, such as race, ethnicity, and socioeconomic status.

The framework stresses the importance of documentation, in addition to that required by the FDA. 15 Patients who receive EUA remdesivir need the medication order and length of course documented in their electronic health record (EHR) to ensure continuity of care across shifts and in case of transfer. At the institutional level, allocation decisions, including randomization, should be documented to permit review and allow transparency. Retrospective review and subgroup analysis will be important to surface problems and inequities. This would ideally be undertaken at both the institutional and state levels, examining how scarce resources are being allocated in the pandemic. 12,14

The remdesivir allocation framework does not provide a mechanism for secondary review ("appeal") of triage decisions. Such mechanisms are crucial when allocation decisions involve complex comparative judgments between patients, as when allocating ventilators under conditions of scarcity. However, implementing the remdesivir framework simply requires that facilities offer the drug to all eligible patients, starting with those in the first tier and moving to the second tier. If the number of eligible patients within a tier exceeds supply of the drug, randomization is used to allocate, rather than comparative judgments between patients. Allocation on these bases is less vulnerable to bias or error.

Our approach had significant limitations, including the lack of robust data from clinical research on which to base clinical allocation criteria. Minnesota's previous guidance on the allocation of resources during a pandemic called for the creation of evidence-based standards to define patient subgroups with the highest need for a clinical intervention, and that would benefit the most from receiving that scarce resource. 11,12 This is required to minimize potential bias and inequities in the distribution of scarce resources. At the time that we created our initial allocation framework, the data needed to create evidence-based allocation criteria were unavailable. Indeed, the data cited in the FDA's EUA --"the topline data" from the NIAID trial and Gilead-sponsored trial 1 --had not yet appeared in print. Although subsequent publication of the NIAID trial data was helpful, those data remain preliminary, 2 and Gilead's open-label study was not a trial of efficacy. 3 Additionally, previous work on pandemic response in Minnesota was developed with extensive expert stakeholder and community input. 11,12 While MCEC's work customarily involves substantial and iterative input from expert stakeholders in the development of guidance, the opportunity for such input was limited in developing the remdesivir framework, due to time constraints. Moreover, while MCEC work on allocation of ventilators and other scarce resources as well as remdesivir has involved dialogue and engagement on issues of inequity, structural racism, disability discrimination, and implicit bias, more systematic engagement with stakeholders and broader community input are warranted.

This remdesivir allocation framework is a living document, subject to revision with the emergence of new and more definitive data to guide use of the medication. Future remdesivir availability will also affect the use of this framework, including the relative availability over time through the FDA's EUA, compassionate use, clinical trials, and ultimately through sale. The Minnesota framework addresses allocation of EUA remdesivir, distinct from compassionate use and research. However, if remdesivir's availability is interrupted, or shifts from EUA to use in clinical trials in combination with other drugs or to sale as an FDA-approved medication, allocation frameworks should adapt to address the ethical issues raised.

A strength of the Minnesota process has been the collection of feedback on each successive version of the remdesivir framework to guide revision. Ethical frameworks for allocation must be evaluated to assess whether they work in practice, accomplish their stated goals, create unexpected negative consequences, and operate equitably across population subgroups, especially subgroups that are historically underserved and more vulnerable to poor health outcomes. At a national scale, we urge systematic collection of information on the range of allocation strategies being deployed, including assessment of how those frameworks are being implemented, with subgroup analysis and outcomes data to evaluate fairness. Such analyses plus robust public input will support development of sound allocation frameworks across the country.

In a public health crisis such as a pandemic, when knowledge is continuously evolving, a wide range of stakeholders may need to collaborate quickly to guide allocation approaches. It may be challenging to mobilize statewide support for an allocation framework on a very short timeline in the absence of longer-term engagement across health care systems, ethics professionals, academic institutions, relevant branches of government, and the community. Ethics advisory groups like MCEC can facilitate this collaboration, acting as a "rapid-response" team to develop guidance during times of urgent need. As this pandemic evolves, additional frameworks are likely to be necessary to address the allocation of a range of possible therapies and prevention strategies including a vaccine. Minnesota's experience with the formulation of this framework for allocation of remdesivir may be useful to other states responding to the rapidly emerging ethical challenges posed by COVID-19.

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved product remdesivir (RDV) for treatment of COVID-19. As the FDA notes, "Remdesivir is a direct acting antiviral that inhibits viral RNA synthesis. It is an investigational drug and is not currently approved for any indication….

[However], it is reasonable to believe that the known and potential benefits of RDV outweigh the known and potential risks of the drug for the treatment of patients hospitalized with severe COVID-19." 1 Minnesota expects to receive a limited quantity of RDV which will be allocated to health care facilities for treatment of patients hospitalized with severe disease. Allocation of this initial limited quantity raises ethical issues addressed by this document.

The hope is that future shipments will be received that will increase the amount of RDV available for future allocation. While this document addresses the May 2020 allocation, the expectation is that a fuller document will subsequently be developed, addressing the ethical issues raised by allocation of future quantities of the medication. 

This document draws upon substantial ethical guidance that had already been developed for public health emergencies in the state of Minnesota, well before the COVID-19 crisis began. This established ethical guidance was created in two projects, sponsored by and completed in partnership with MDH: the Minnesota Pandemic Ethics Project (www.health.state.mn.us/communities/ep/surge/crisis/panethics.html), and Ethical Considerations -Crisis Standards of Care (www.health.state.mn.us/communities/ep/surge/crisis/ethical.html). The development of that ethical guidance involved significant stakeholder consultation and wide community engagement. Community engagement forums included discussion of allocation objectives, criteria for allocation, and strategies to promote equity in access and address health disparities.

In the COVID-19 pandemic, as in other public health emergencies, response must focus on the overall benefit to the population, to try to save the most lives possible while also respecting rights and promoting fairness across our population.

This ethical framework for COVID-19 response is grounded in the fundamental ethical commitment that the response to a pandemic will pursue Minnesotans' common good in ways that: ▪ are accountable, transparent, and worthy of trust; ▪ promote solidarity and mutual responsibility; and ▪ respond to needs respectfully, fairly, effectively, and efficiently.

To honor these fundamental value commitments, pandemic response must promote Minnesotans' common good by balancing three ethical objectives: ▪ protect the population's health by reducing mortality and serious morbidity; ▪ respect individuals and groups; and ▪ strive for fairness and protect against systematic unfairness and inequity.

Allocation of scarce resources should be grounded in maximizing the number of lives saved, taking into account both risk and expectation of benefit. Evaluation of clinical prognosis, construed here as survival to discharge from an acute care facility, should be based upon wellaccepted clinical tools and individualized assessment. This framework provides guidance about allocation to health care facilities across the state, as well as to patients within a given facility.

In existing ethical guidance for public health emergency response in Minnesota, recommended allocation of antivirals has included some prioritization of key workers, both due to considerations of reciprocity (what is owed to workers by virtue of the risk they take on) and instrumentality (what is owed to workers based on their role in response and recovery). Given extreme scarcity and the time pressures associated with initial RDV allocations, it may be logistically impractical to satisfy these obligations -and so key worker status should not be considered in the May 2020 RDV allocations. However, future documents should address previous guidance providing some priority for key workers as more resources become available.

Under the Emergency Use Authorization (EUA) for remdesivir, the recommended dose for adults and pediatric patients weighing >40 kg on mechanical ventilation or ECMO is a single loading of 200mg on Day 1 followed by 100mg once daily for Days 2 through 10 (for a total 10day course). The recommended dose for adults and pediatric patients weighing >40 kg not on mechanical ventilation or ECMO is a single loading dose of 200mg on Day 1 followed by 100mg once daily for Days 2 through 5 (for a total 5-day course). At five days, patients who are not mechanically ventilated or on ECMO should be evaluated for discontinuation of RDV with extra doses reallocated to other patients. In general, patients who have started a course of RDV who later no longer meet clinical criteria for eligibility because of worsening kidney or liver function should be considered for discontinuation and reallocation of RDV. It should not be discontinued solely for purposes of reallocating to other patients.

Ethical strategy for distribution throughout the state:

Distribution of RDV to health care facilities across the state should be proportional to the total number of COVID-positive patients currently admitted to the facility who are not currently on RDV for any reason (e.g., under compassionate use, a clinical trial, or previous allocations of RDV). In other words, more resources should be sent to facilities with greater numbers of prioritized recipients, so that patients at highest priority have maximal access to the scarce resources.

Process for allocation among facilities in Minnesota:

For allocation of the May 2020 allocations of RDV to health care facilities, MDH should estimate how many patients at each facility (or system, if facility data are unavailable) fit the allocation criteria listed above. Based on those numbers, MDH should calculate the proportion of that total associated with each facility (or system), and distribute the relevant proportion of the total supply of RDV to each facility (or system). If the state's allocation of RDV goes to a system instead of a single facility, that system should allocate proportionately to its facilities based on the number of prioritized patients in each facility.

In the event that a patient receives RDV or is ordered RDV under this framework and is later transferred to another facility inside or outside of Minnesota, the remainder of the course should follow that patient. Systems that have facilities located outside of Minnesota should only be allocated RDV for their in-state facilities.

Each facility (or system) should identify points of communication for MDH to contact with information about 1) pending shipments and 2) number of patients currently being treated with RDV for any reason. This guidance recommends that RDV status be recorded in the Electronic Health Record for ease of access to information.

Facilities may have more patients who are prioritized for access to RDV than available doses. As noted below, allocation among equally prioritized patients within facilities should be by a fair, random process. In order to maximize benefit of this resource, no courses from the May 2020 allocation should be held in reserve for future use. All courses should be immediately allocated. If facilities have RDV doses left over after an allocation window of 72 hours from receipt of the shipment at the facility, they should contact MDH (Sarah Lim, sarah.lim@state.mn.us).

The patients receiving the highest priority for allocation of RDV are: Patients with laboratoryconfirmed COVID-19 (by RT-PCR testing on a respiratory specimen) who are not already on RDV (e.g., for clinical trials or compassionate use) and 1) are on advanced respiratory support (highflow nasal cannula; CPAP; BiPAP) OR 2) who have three of the four characteristics: ▪ < 94% oxygen saturation on room air ▪ Respiratory rate > 30 ▪ Lung infiltrates on imaging ▪ Using supplemental oxygen Patients should meet other clinical inclusion criteria as specified by the FDA EUA for RDV (GFR ≥30ml/min, ALT < 5 times upper limit of normal).

When patients are otherwise of equal priority in the highest priority group of patients (i.e., there is no substantial difference in risk and likelihood of benefit) and there is not sufficient RDV for all patients in this group, the Triage Officer or Team should use a random process to allocate the resource (as explained below).

If facilities have met the needs of the highest priority group of patients, facilities should then allocate RDV based on the following criteria:

▪ Patients with laboratory-confirmed COVID-19 (by RT-PCR testing on a respiratory specimen) who are not already on RDV (e.g., for clinical trials or compassionate use) and who have been mechanically ventilated for 5 days or less or are on ECMO for 5 days or less. Patients should meet other clinical inclusion criteria as specified by the FDA EUA for RDV (GFR ≥30ml/min, ALT < 5 times upper limit of normal).

When patients are otherwise of equal priority within a priority group of patients (i.e., there is no substantial difference in risk and likelihood of benefit) and there is not sufficient RDV for all patients in that group, the Triage Officer or Team should use a random process to allocate the resource (as explained below).

In both priority groups, in addition to prognosis of surviving current illness to hospital discharge, allocation decisions should consider whether the patient is imminently and irreversibly dying or terminally ill with life expectancy under 6 months (e.g., eligible for admission to hospice). Given the scarcity of supply of RDV, patients in this group should not currently receive priority for access.

In order to maximize benefit of this resource, no courses from the May 2020 allocations should be held in reserve for future use. 

On intake, clinical teams should discuss the patient's interest in receiving therapies not yet approved by the FDA but available under an EUA, should they become available, and document the discussion in the EHR. In addition, patients may be asked whether they would be interested in receiving investigational therapies, if they qualify for access through compassionate use or a clinical trial. (Access and consent to those investigational uses are not addressed by this framework.) Patients should be informed if they have been deemed eligible for and selected to receive an RDV course under this RDV framework, even if they had previously indicated they were not interested in receiving unapproved therapies. A patient who is capable of decision-making is entitled to partner with their care team in deciding whether to consent to administration of RDV. Patients should be informed that RDV is not FDA-approved but is available under an Emergency Use Authorization. For patients who are not capable of making decisions, their authorized decision-maker should be consulted. If the patient lacks decision-making capacity but no authorized decision-maker is available, clinicians should allocate the RDV if the patient is eligible in keeping with the best interests of the patient, unless the patient previously refused to consent to unapproved therapies. The authorized decision-maker should be the person appointed by the patient to make decisions on their behalf. If the patient has not indicated who that person should be, the clinical team should work with the patient's spouse, partner, family, or close friend. Clinicians and health care organizations should work to follow Minnesota guidance and law on surrogate decision-making.

Facilities should make sure to note in the patient's records how to reach the authorized decision-maker rapidly.

Children and pregnant women are currently eligible to receive RDV through compassionate use from Gilead and so will not be prioritized for the May 2020 allocations.

Patients who are already receiving RDV (e.g., through clinical trials or compassionate use) will not be eligible to receive doses from this round of drug allocation.

Key workers will not receive prioritization during this round of allocation, for the reasons noted earlier in the document.

Allocation decisions should not consider or be based upon:

▪ Race, ethnicity, gender, gender identity, sexual orientation or preference, religion, citizenship or immigration status, or socioeconomic status; ▪ Ability to pay;

▪ Age as a criterion in and of itself (this does not limit consideration of a patient's age in clinical prognostication of likelihood to survive to hospital discharge);

▪ Disability status or comorbid condition(s) as a criterion in and of itself (this does not limit consideration of a patient's physical condition in clinical prognostication of likelihood to survive to hospital discharge);

▪ Predictions about baseline life expectancy beyond the current episode of care (i.e., life expectancy if the patient were not facing the current crisis), unless the patient is imminently and irreversibly dying or terminally ill with life expectancy under 6 months (e.g., eligible for admission to hospice);

▪ First-come, first-served (should not distinguish between patients when treatment has not yet been started on equivalent patients);

▪ Judgments that some people have greater "quality of life" than others;

▪ Judgments that some people have greater "social value" than others.

Separation of roles --triage decision-making and bedside care: Randomization decisions should be made by a Triage Officer or Team that is separate from the clinicians providing care at the bedside. This approach to decision-making promotes the ability of bedside clinicians to advocate for their patients, thus protecting the integrity of the patient/provider relationship. It also helps to ensure that allocation decisions are made fairly, consistently, and based on objective data to allow comparisons across cases. The separation of roles does not imply that the Triage Officer or Team may not communicate with treating clinicians. For example, the Triage Officer or Team may need to consult the treating clinician to clarify factors relevant to the triage decision. In any communication between the treating clinician and Triage Officer or Team, all should be mindful that, to the extent possible, the Triage Officer or Team should not be provided with patient characteristics identified above as impermissible to consider in allocation decisions. While bedside clinicians will not make allocation decisions, they will be

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The authors are indebted to the participants in the Minnesota COVID Ethics Collaborative (MCEC) as well as those in the Minnesota Critical Care Compact for input in the preparation and subsequent revisions of the remdesivir allocation framework. Participants in those groups are not responsible for the contents of this article. Thanks to Joy Benn of the Minnesota Hospital Association for expert coordination of MCEC and to Andrea Martin of the University of Minnesota for additional support. Aron Mozes, JD candidate, University of Minnesota, provided research assistance for this article.

Ethical strategy for distribution within a facility:Clinical prognosis should ground allocation decisions. Prognosis should be understood to include both need for the resource (i.e., risk of serious morbidity or mortality if the patient were not to receive the resource), and the likelihood that the patient will benefit from access to the resource by recovery to hospital discharge. Substantial differences in prognosis are what is ethically relevant in differentiating between patients; small differences should be viewed as morally equivalent and should not be used to allocate resources to or withhold resources from patients.After discussion with infectious disease experts and members of the MCEC, and updated with preliminary data from the published Beigel et al. RDV trial published on May 22 2 , clinical criteria for the May 2020 allocation was determined based on risk and likelihood of greatest benefit. 7 expected to follow the directives of the Triage Officer or Team, so that resources may be ethically stewarded.

triage process for the May 2020 shipment of RDV to maintain separation of roles, for example using the administrative head of pharmacy to randomize among eligible patients.

Patients who receive RDV should have the order (including length of course) documented in the patient's Electronic Health Record (EHR). Allocation decisions should be logged and recorded by facility to allow for transparency and retrospective review. This log should include which patients were eligible for RDV, which patients received the RDV allocation, and how randomization occurred. Documentation is important to ensure appropriate care of the patient across clinicians and shifts, to ensure transparency and accountability to the patient and family, to allow Triage processes to work properly, and to enable retrospective review to spot and resolve problems.