Antivirals for Pandemic Influenza: Guidance on Developing a Distribution and Dispensing Program (2008)

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Summary I n the event of an influenza pandemic, antiviral medication will be one of several strategies deployed to contain the outbreak and to mitigate hospitalization and mortality rates. Although a vaccine well-matched to the pandemic viral strain would be the most effective tool in respond- ing to a pandemic, such a vaccine will not become available for several months after the pandemic begins due to time needed to develop and produce the vaccine. Antivirals are a hoped-for bridge to availability of vaccine. The federal government, public health agencies at all levels, and their partners are planning to implement a program of antiviral distribution and dispensing during the first wave of the pandemic for treatment and perhaps prevention. The main antiviral drugs stockpiled by the federal and state governments are the neuraminidase inhibitors oseltamivir and zanamivir. These antivirals have been approved by the Food and Drug Administration (FDA) for use in both treating and preventing seasonal influenza. The Institute of Medicine Committee on Implementation of Antivi- ral Medication Strategies for an Influenza Pandemic was charged with considering best practices and policies for implementing a program of treatment and prophylaxis. The complete statement of task is provided in Box S-1. Planning for an influenza pandemic recognizes two basic facts: uncer- tainty and scarcity. As a starting point, the committee acknowledged that the process of planning is complicated by many unknowns, and that  

 ANTIVIRALS FOR PANDEMIC INFLUENZA BOX S-1 Statement of Task An Institute of Medicine committee would plan and convene a workshop of state and local pandemic influenza planners, as well as national and relevant international influenza experts, to consider best practices and policies for imple- menting a pandemic influenza antiviral drug program. Components of the program to be addressed include treatment of cases, post-exposure prophylaxis for their household contacts, and prophylaxis of “front-line” health care workers and emer- gency services personnel. With respect to treatment of cases and post-exposure prophylaxis of their household contacts, key planning issues include, but are not limited to, determining where drugs are dispensed; allocation and distribution of drugs to those sites; diagnostic approach for cases; strategy to enumerate house- hold contacts and assess appropriateness of dispensing drugs for them; potential regulatory barriers to dispensing; and monitoring antiviral drug use and safety. With respect to prophylaxis for targeted health care and emergency services personnel, key issues include, but are not limited to, determining where drugs are dispensed; potential regulatory barriers to dispensing; labor issues that may arise from target­ ing some workers, but not others; and monitoring antiviral drug use and safety. The committee will review current state plans and lessons learned from drills and exercises, and will explore the challenges and barriers to rapid and efficient distri- bution of the drugs for treatment and prophylaxis in the general population and in targeted occupationally defined groups. The committee will issue a brief report with conclusions and recommendations regarding components of an effective antiviral program for patients and their household contacts and for prophylaxis of health care and emergency services personnel. the context of planning may evolve considerably over the coming years, requiring frequent revisiting of planning assumptions, and adapting of policies and plans. For example, it is not known whether the antivirals that are effective against seasonal influenza will be similarly effective against a pandemic strain, and different doses and regimens may be needed for effective treatment and prophylaxis (Hayden and Pavia, 2006; WHO, 2008). The geographic origin (that may or may not be outside the United States) and epidemiologic profile of the disease will only be known once the pandemic has begun and patterns of attack and transmis- sion have become clear. The extent and speed of emerging antiviral resis- tance also may limit drugs’ effectiveness. For discussion and planning purposes, the committee found it helpful to think about the implications of a severe, 1918-type pandemic, occurring in waves, characterized by a mortality rate considerably higher than that of seasonal influenza and a different than usual epidemiologic profile. 

SUMMARY  This committee’s work was informed by relevant documents devel- oped by federal agencies and by the state and local public health commu- nity, and by some of the information gathered at the committee’s public meetings. Peer-reviewed scientific evidence is largely limited to data on the effectiveness and safety of antivirals, and even that body of data is far short of definitive and continues to evolve as do the influenza viruses of concern. Little to no empirical evidence is available on the logistical aspects of antiviral dispensing and other dimensions of an antivirals pro- gram. For these reasons, the basis for the recommendations provided in this report largely represents the expert judgment of a diverse committee based on the limited or incomplete evidence described above. Moreover, the committee recognizes that parts of this report may only be valid for a few years if major changes (e.g., vaccine technology and availability, antiviral stockpile size, resistance) occur, but the committee believes that some of the parameters it outlines to help guide antiviral dispensing will continue to have relevance. To help facilitate its thinking about the circumstances that would shape a program of distribution and dispensing, the committee describes three simple stockpile scenarios that have different implications for planning depending on the severity of the pandemic: (A) where the supply of antivirals is sufficient either for treating most cases or providing a considerable level of prophylaxis or a combination of both uses but targeting considerably smaller groups, (B) where sufficient antivirals are available for treatment and narrowly tar- geted prophylaxis of certain groups with occupational exposure, and (C) where enough antivirals are available to support treatment and a broad program of occupational and perhaps household prophylaxis. Responding to the charge was difficult. Ultimately, the committee found that antiviral dispensing strategies, including selection of sites and priority groups, are inextricably linked with the amount of antivirals currently available and national goals for antiviral use. For reasons that include the limited antiviral drug stockpile and the not yet clear goals for antiviral use, as discussed in greater detail in Chapter 2, the committee was unable to provide specific guidance in regard to best methods and sites for dispensing. The committee also concluded that identifying pri- ority groups to receive antiviral treatment and prophylaxis (depending on national goals) requires a process of national public and stakeholder engagement similar to that undertaken for pandemic influenza vaccine   Theseinclude some documents that are available in draft form (the Department of Health and Human Services’ November 6 and 20, 2007, draft guidance documents) or that have been developed as a basis for further discussion (the prioritization scheme for antiviral use developed by the National Vaccine Advisory Committee and included in the 2005 National Pandemic Influenza Plan). 

 ANTIVIRALS FOR PANDEMIC INFLUENZA prioritization. Moreover, the committee believes that final determina- tions regarding priority groups for antiviral use can only be made when data about epidemiologic features of the disease become available (e.g., what age groups have the highest attack rates and mortality rates). In Chapter 3, the committee recommends a process and an entity for real- time decision making, including about prioritization and adjustments based on information emerging during the pandemic. In Chapter 4, the report recommends a first level of prioritization for prophylaxis, discusses characteristics of groups with occupational or household exposure that require consideration, describes advantages and disadvantages of a range of dispensing sites, and examines some legal issues relevant to planning and implementing antiviral dispensing strategies. The committee noted the planning assumptions made by federal government planners to address uncertainty. The following assumptions concerning the pandemic and antiviral drugs establish the context for the committee’s discussion of what is needed to effectively implement an antiviral drug program. 1. A severe pandemic (more so than one that is milder) will require a pre-existing ethical framework to guide decision making about prioritization, so that individual and societal interests and goals are effectively, efficiently, and fairly pursued. 2. Antivirals will be used in conjunction with non-pharmaceutical interventions for which the evidence of effectiveness currently is limited or unclear. 3. Resistance to neuraminidase inhibitors may weaken pandemic influenza response. 4. An increase in dosage and/or length of treatment and prophy- laxis (WHO, 2008) may be needed to ensure effectiveness (in the face of resistance and new epidemiologic information), and this will affect the supply of antivirals. 5. Public–private collaboration on a large scale (e.g., private employer antiviral stockpiling for dispensing to large enough groups to enhance flexibility in use of public-sector stockpiles) is unlikely, due to administrative constraints, fiscal limits, and other private-sector concerns about stockpiling. 6. Interjurisdictional coordination in regard to antiviral dispensing (and other aspects of pandemic response) is likely to be chal- lenged by known and unforeseen differences in local circum- stances and expectations. 7. Budget challenges, opportunity costs, and other cost–benefit con- siderations at the state level may affect some jurisdictions’ pur- chasing capability and willingness to stockpile antivirals at levels recommended by federal authorities (ASTHO, 2008). 

SUMMARY  Recommendations Based on federal government documents, it is not yet clear whether the goal of antiviral use is treatment, or a combination of treatment and prophylaxis. The Homeland Security Council National Strategy for Pan- demic Influenza states that “current plans propose using antiviral medica- tion stockpiles only for treatment once a pandemic is underway. Prophy- lactic use of antiviral medications will be reserved for initial containment efforts and other highly select circumstances” (Homeland Security Coun- cil, 2006:106). The Department of Health and Human Services (DHHS) Pandemic Influenza Plan provides “recommendations . . . on the distribu- tion and use of antivirals for treatment and prophylaxis throughout the pandemic phases” (DHHS, 2005:11). The DHHS draft proposed guidance on antiviral use similarly describes use of antivirals for treatment and for a potential range of prophylaxis activities. DHHS references to the stock- pile, however, describe it as “antiviral treatment courses for 25 percent of the U.S. population or 81 million treatment courses” (Vanderwagen, 2007), and the DHHS Secretary’s Pandemic Influenza Update IV (DHHS, 2007c) refers to the stockpile as “81 million treatment courses,” which “include 6 million treatment courses set aside for the early stages of an emerging pandemic.” Recommendation 2-1: The committee recommends that the fed- eral government clarify the national goals for antiviral use in an influenza pandemic. If these goals include treatment of all antici- pated cases and a level of prophylaxis, fiscal appropriations will be needed to expand the national stockpile to meet these goals. Unlike federal stockpiles, state and private-sector stockpiles are not covered under the Shelf-Life Extension Program that tests batches of drugs several months before expiration to determine their viability. This means that properly stored antiviral drugs purchased by non-federal enti- ties may expire and need to be discarded before they are used. Given the considerable purchase and opportunity costs and the limited availability of antivirals, it is important to address this issue. Recommendation 2-2: The committee recommends that the federal government’s Shelf-Life Extension Program be expanded to include other public- and private-sector entities that are stockpiling antivi- rals for use in an influenza pandemic.   Recommendations are numbered by the chapter where they occur and their order in the chapter. There are no recommendations in Chapter 1, so the first recommendation, provided in Chapter 2, is Recommendation 2-1. 

 ANTIVIRALS FOR PANDEMIC INFLUENZA A pandemic may occur at a time when non-federal public- or ­private- sector organizations have on hand expired, but potentially viable, anti- viral stocks. Recommendation 2-3: The committee further recommends that the Department of Health and Human Services develop a process to use the knowledge acquired by the Food and Drug Administration in the operation of the Shelf-Life Extension Program to facilitate the use of properly stored, recently expired medications that exist in supplies outside the Shelf-Life Extension Program in the event these medications are needed because of a shortage. Some private-sector employers are planning to stockpile antivirals for use by some or all of their employees and others are taking steps to pre-position antivirals with employees in advance of an influenza pan- demic. Coordinating with state and local public health agencies could be mutually beneficial (increased flexibility for public stockpiles, sharing of private-sector know-how on distribution, etc.). Also, the use of similar standards for prioritizing scarce resources in the public and private sec- tors could help avoid public outcry and confusion. Recommendation 2-4: To promote mutual trust, collaboration, and coordination, memorandums of understanding or similar agreements should be developed between public health agencies and private-sector entities in their jurisdictions. During the pre- pandemic period and in the early stages of a pandemic, such collab- orations could facilitate information sharing and awareness of state and local recommendations regarding anticipated best practices in public health and standards of care in response to an influenza pandemic. (These may include prioritization schemes, guidelines for initial treatment of suspected cases, initial post-exposure pro- phylaxis, reporting of adverse events concerning antivirals, and coordination with state, tribal, and local officials as to who has been given medication.) An influenza pandemic will require making difficult value-laden deci-   This could perhaps include antivirals in the federal stockpile, depending on the threshold for viability established by the Shelf-Life Extension Program and evidence-based decisions about the usefulness of these drugs.   As part of this program, a collaborative effort between FDA and the Department of De- fense, FDA Office of Regulatory Affairs “laboratories test product samples, and in coopera- tion with FDA’s Center for Drug Evaluation and Research, determine if the expiration date for the lot of the product can be extended and for how long” (FDA, 2007a). 

SUMMARY  sions in the context of scarce resources, evolving scientific and other infor- mation, and great societal stress and concern. Beginning a dialogue about ethics in advance, and beginning to outline an ethical framework may prove helpful during response to a pandemic, when time for thoughtful deliberation will be limited. Recommendation 3-1: The committee recommends that the federal government in collaboration with state, tribal, and local govern- ments support the development of a national ethical framework to guide the allocation of antivirals (and other scarce health resources) during a severe influenza pandemic. Developing the framework should incorporate processes to obtain input from the public and a wide array of stakeholders. There is no advisory body analogous to the Advisory Committee on Immunization Practices to provide timely scientific advice to the federal government and its partners during the implementation of an antiviral program and other dimensions of pandemic response, including recom- mendations for rapid mid-course adjustments in antiviral use strategies due to changes in the epidemiology and virology of the disease and its agent. Recommendation 3-2: The committee recommends that as soon as possible a federal advisory body be formed to advise the federal government and its partners on the planning and implementation of public health and medical responses to an influenza pandemic, including antiviral use. Options for establishing an advisory body include creating a subcommittee under the National Biodefense Science Board or creating a new federal advisory committee to the Department of Health and Human Services. Communication is a critical dimension of preparing for antiviral dis- tribution and dispensing, with particular attention to the needs of cultur- ally and linguistically diverse communities. Recommendation 3-3: The committee recommends that state, tribal, and local public health officials preparing for an influenza pandemic develop partnerships with (1) the media, including ethnic media; (2) leaders of local faith communities; (3) community-based clinics; and (4) other trusted organizations and community leaders to con- vey vital public health information clearly, simply, and in a manner that respects and reflects cultural and linguistic differences. Although DHHS has facilitated a national dialogue and public 

 ANTIVIRALS FOR PANDEMIC INFLUENZA engagement process on prioritization of pandemic influenza vaccine, an analogous process has not been undertaken to consider priorities in the use of antiviral drugs. Recommendation 4-1: The committee recommends that in the pre- pandemic period, the Department of Health and Human Services undertake an effort similar to that for influenza vaccine priorities— national in scope, inclusive of diverse populations and viewpoints, and in keeping with a shared ethical framework—to discuss and develop a prioritization scheme for antiviral treatment and prophy- laxis that is capable of adjustments in real-time in response to the influenza pandemic. Prophylaxis of select health care workers and others with occupa- tional exposures will be a necessary component of an antiviral program if supplies are adequate to allow this. Decisions about types and extent of prophylaxis for groups with occu- pational exposure must take into consideration the potential for facilitat- ing the development of resistance, currently inadequate supply, drug risk and benefit, and unknown epidemiology and virology of the disease and its agent. In order to use scarce antivirals sparingly and strategically, based on available epidemiologic data and local circumstances, the com- mittee recommends the following: Recommendation 4-2: The committee recommends that pandemic influenza planners at all levels make outbreak prophylaxis for health care and emergency personnel who are in short supply and will have repeated and difficult-to-control exposure a first priority for prophylactic antiviral use. Post-exposure prophylaxis for other health care personnel and emergency responders should be a sec- ond priority. Post-exposure prophylaxis of household contacts of infected individuals should be a third priority if stockpiled antivi- rals are insufficient to meet all prophylaxis objectives. Recommendation 4-3: The committee recommends that efforts be made to minimize the need for outbreak prophylaxis among health care and emergency responders, and efficiently allocate scarce health resources. Necessary measures include proper and consistent use of personal protective equipment (PPE) and grouping of workers in subsets to stagger their exposure to infected patients, thus reducing   See Chapter 3. 

SUMMARY  the numbers who need prophylaxis at any given time and shorten- ing the duration of needed prophylaxis. A pandemic would place unprecedented demands on most existing public health information systems that are being considered for use to track antiviral dispensing. Despite the many barriers, systems for tracking who gets antivirals will be needed, especially in the context of a severe pandemic and with limited supplies. Furthermore, use and expansion of existing systems may constitute the best use of resources. Finally, it is essential to do this work before the pandemic begins. Recommendation 4-4: The committee recommends that the Depart- ment of Health and Human Services support and fund public health agencies to develop or expand information systems for tracking dis- pensed antivirals. The development or expansion of these systems should make use of existing information resources or systems, con- sider information technology needs for other dimensions of pan- demic influenza response, comply with Centers for Disease Control and Prevention standards, and be interoperable and robust. For reporting adverse events related to antiviral use, the proposed DHHS draft guidance states that the FDA Adverse Event Reporting System (AERS)/Medwatch should be used. This system is passive and not ideally suited to rapidly capture, interpret, and convey information needed to evaluate a course of action. AERS may not address the need of state and local jurisdictions to monitor and respond to adverse events. Thus, public health agencies and their partners may need some additional measures to prepare for and respond to safety signals, whether real or perceived. It may not be necessary or realistic to attempt to gather com- prehensive information about each antiviral drug-related adverse event, but rather, to gather statistically accurate information. Recommendation 4-5: The committee recommends that the Depart- ment of Health and Human Services consider options in addition to the Food and Drug Administration Adverse Event Reporting System to capture adverse events resulting from use of antiviral drugs to ensure active and timely reporting. One option is a network of sentinel sites that can collect data that are representative of antiviral use nationally. Preparing for pandemic influenza and other emergency events requires not only planning but practicing the use of those plans. The Centers for Disease Control and Prevention (CDC) public health pre- 

10 ANTIVIRALS FOR PANDEMIC INFLUENZA paredness and Strategic National Stockpile (SNS) guidance documents to grantees (states, territories, and three cities) require them to practice their plans in table-top exercises and subsequent full-scale exercises. However, pandemic preparedness plans or parts of these plans, such as antiviral dis- pensing plans, also are used by some grantees to respond to disease out- breaks and other public health emergencies, and may help them test and improve the implementation of a wide range of distribution and dispens- ing sites and mechanisms, in addition to the well-known and exercised SNS point-of-dispensing. The committee understands that aspects of such activities may be used to meet the performance measures requirement in CDC guidance, but not the exercise requirement. Recommendation 4-6: The committee recommends that federal pandemic influenza grant guidance explicitly state that jurisdic- tions receiving federal funding may fulfill the exercise requirement through the implementation of response to actual biologic emer- gency situations or similar events, if the appropriate benchmarks are used, performance is evaluated, and necessary corrective action is taken. Closing Observations Implementation of an antivirals program for pandemic influenza, whether it occurs in the near or distant future will need to take into account multiple factors, many of which are evolving or will only become apparent in a pandemic (supply of antivirals, shelf-life, resistance, vaccine technology, roles of stakeholders). The epidemiologic characteristics of the pandemic strain—for example, age of greatest impact and/or mortality, mode of spread, rapidity of development of resistance—constitute large unknowns that will affect when, how, and which individuals are provided antiviral medication. Regardless of the final shape of the pandemic, it is clear to the committee that many of these issues need to be prepared for in advance and provide a basis for all decisions. Several overarching goals need to be kept in the forefront: developing in advance an ethical framework, communication and education of the public with clear and consistent messages, the need to reconcile actual supply and antiviral program goals, and flexibility to on the one hand react to the changes in the course of the pandemic and on the other hand, address the diverse needs of localities.