Updated Preparedness and Response Framework for Influenza Pandemics

Prepared by

Rachel Holloway1

Sonja A. Rasmussen, MD1

Stephanie Zaza, MD2

Nancy J. Cox, PhD3

Daniel B. Jernigan, MD3

with the Influenza Pandemic Framework Workgroup

1Influenza Coordination Unit, Office of Infectious Diseases

2Division of Adolescent and School Health, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

3Influenza Division, National Center for Immunization and Respiratory Diseases

Corresponding preparer: Sonja A. Rasmussen, MD, CDC. Telephone: 404-639-2297; E-mail: [email protected].

Summary

The complexities of planning for and responding to the emergence of novel influenza viruses emphasize the need for systematic frameworks to describe the progression of the event; weigh the risk of emergence and potential public health impact; evaluate transmissibility, antiviral resistance, and severity; and make decisions about interventions. On the basis of experience from recent influenza responses, CDC has updated its framework to describe influenza pandemic progression using six intervals (two prepandemic and four pandemic intervals) and eight domains. This updated framework can be used for influenza pandemic planning and serves as recommendations for risk assessment, decision-making, and action in the United States. The updated framework replaces the U.S. federal government stages from the 2006 implementation plan for the National Strategy for Pandemic Influenza (US Homeland Security Council. National strategy for pandemic influenza: implementation plan. Washington, DC: US Homeland Security Council; 2006. Available at http://www.flu.gov/planning-preparedness/federal/pandemic-influenza-implementation.pdf). The six intervals of the updated framework are as follows: 1) investigation of cases of novel influenza, 2) recognition of increased potential for ongoing transmission, 3) initiation of a pandemic wave, 4) acceleration of a pandemic wave, 5) deceleration of a pandemic wave, and 6) preparation for future pandemic waves. The following eight domains are used to organize response efforts within each interval: incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination.

Compared with the previous U.S. government stages, this updated framework provides greater detail and clarity regarding the potential timing of key decisions and actions aimed at slowing the spread and mitigating the impact of an emerging pandemic. Use of this updated framework is anticipated to improve pandemic preparedness and response in the United States. Activities and decisions during a response are event-specific. These intervals serve as a reference for public health decision-making by federal, state, and local health authorities in the United States during an influenza pandemic and are not meant to be prescriptive or comprehensive. This framework incorporates information from newly developed tools for pandemic planning and response, including the Influenza Risk Assessment Tool and the Pandemic Severity Assessment Framework, and has been aligned with the pandemic phases restructured in 2013 by the World Health Organization.

Introduction

Planning for and responding to the range of possible consequences following the emergence of a novel influenza A virus is complex. These viruses can spread quickly and explosively worldwide, as did the influenza pandemics in 1918, 1957, 1968, and 2009 (1,2); cause limited outbreaks, such as the influenza A(H3N2) variant (H3N2v) virus in the United States associated with agricultural fairs in the summer months of 2011, 2012, and 2013 (3); or continue causing limited animal-to-human transmission of virus, such as the influenza A(H5N1) and influenza A(H7N9) viruses in Asia (4,5). Furthermore, novel influenza A viruses, even when transmissible in a closed setting, do not always result in a pandemic, such as the 1976 influenza A(H1N1) outbreak in Fort Dix, New Jersey, and the 2011–2013 H3N2v outbreak in the United States (3,6). Identifying and responding to this wide range of situations require systematic frameworks that describe the progression of events; weigh the risk of emergence and potential public health impact of the novel virus; evaluate the potential for ongoing transmissibility, antiviral resistance, and disease severity; and can be used to develop time-sensitive decisions about interventions (e.g., community mitigation measures, medical countermeasures, and vaccines). Preparedness and response frameworks provide a common basis for planning across different jurisdictions and ensure transparency in decisions made and actions taken.

Significant progress has been made toward developing pandemic plans, as well as preparedness and response frameworks, during the past decade. Efforts by the World Health Organization (WHO), CDC, other U.S. government agencies, and state and local jurisdictions have addressed pandemic preparedness planning. Lessons regarding gaps in U.S. influenza decision-making frameworks have become evident with each event and exercise (7). The recent emergence of human disease caused by H3N2v in the United States (3) and H7N9 in China (5) has demonstrated the need to align existing documents and frameworks into one useful tool that can be used to guide ongoing planning and response efforts.

Background

Frameworks describing the progression of influenza pandemics have evolved over time. The 2005 WHO global pandemic plan introduced the concept of pandemic phases (8). Six phases were used to describe the evolving risk of efficient human-to-human transmission as a basis for defining a pandemic.

In November 2005, the president of the United States released a national strategy for pandemic influenza (9), and the associated implementation plan was released in May 2006 (10). These documents introduced the concept of using stages to determine the response to pandemic influenza, including stage 0 (new domestic animal outbreak in an at-risk country), stages 1–3 (human outbreaks suspected, confirmed, and widespread overseas), and stages 4–6 (first case in a human in North America, spread throughout the United States, and recovery and preparation for subsequent waves). The U.S. government stages provided greater specificity for U.S. preparedness and response efforts than the WHO phases and facilitated initial planning efforts by identifying objectives, actions, policy decisions, and message considerations for each stage. The stages provided a general overview of the approach to a pandemic response; however, detailed pandemic response planning requires a greater level of specificity to determine federal, state, and local response actions during the course of a pandemic. In addition, the stages framework presumed geographic spread from outside the United States into the United States. In 2007, CDC developed the CDC intervals, a common framework from which CDC and other federal, state, and local governments and agencies could plan and coordinate their pandemic response actions. The 2007 CDC intervals refined the stages framework in the following ways:

• Provided greater detail to reflect the progression of a pandemic, including when decisions and actions might occur
• Provided improved definitions to identify the transition points between intervals to reduce variability in interpretation
• Considered that pandemic influenza might emerge inside or outside of the United States
• Accommodated the likely asynchrony of pandemic stages and progression in different jurisdictions to allow for local, state, regional, and national actions appropriate to jurisdiction-specific conditions
• Provided a structure that allowed for planning for multiple waves

The resulting document (Proposal for the Use of Intervals, Triggers, and Actions in CDC Pandemic Influenza Planning, 2008) was revised, published as an appendix to the U.S. Department of Health and Human Services pandemic influenza operational plan (11), and used during the 2009 H1N1 pandemic to describe progression of the pandemic and to help guide the response. This report provides an update to the 2008 framework to reflect experiences with 2009 H1N1 and recent responses to localized outbreaks of novel influenza A viruses.

The revised framework also incorporates the recently developed Influenza Risk Assessment Tool (IRAT) (12) and Pandemic Severity Assessment Framework (PSAF) (13). IRAT makes an assessment of potential pandemic risk for a novel virus on the basis of the likelihood of emergence and the public health impact if it were to emerge. Emergence refers to the risk of a novel (i.e., new in humans) influenza virus acquiring the ability to spread easily and efficiently in humans. Public health impact refers to the potential severity of human disease caused by the virus (e.g., deaths and hospitalizations), as well as the impact on society (e.g., missed workdays, strain on hospital capacity and resources, and interruption of basic public services) if a novel influenza virus were to begin spreading efficiently and sustainably among humans (12). After a novel virus has achieved efficient and sustained transmission, PSAF can be used to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences. PSAF replaces the Pandemic Severity Index as a severity assessment tool (13).

In 2013, WHO released interim guidance for pandemic influenza risk management, which includes restructured WHO phases (14). The revised WHO phases are based on virologic, epidemiologic, and clinical data. WHO uses the phases to describe evolving situations pertaining to the circulation of novel influenza viruses. The WHO phases are distinct from declarations of either a public health emergency of international concern (15) or a pandemic and are not specifically aligned with national risk management decisions. In the interim guidance, WHO strongly advises countries to use local circumstances and information provided by the WHO global assessments to develop their own national risk assessments (13).

The framework described in this report is a revision of the 2008 CDC interim guidance (11) to 1) update the novel influenza virus pandemic intervals as the basis for U.S. planning efforts; 2) align the intervals with the new WHO phases; 3) add and align tools to aid in decision-making and actions throughout the progression of an event; 4) serve as recommendations for U.S. risk assessment, decision-making, and action as advised by WHO; and 5) replace the U.S. government stages with six intervals for pandemic influenza planning. This framework is designed for decision-making by federal, state, and local health authorities and is not meant to be prescriptive or comprehensive.

The framework was reviewed for accuracy, feasibility, and clarity by several stakeholders, including representatives of the Association of State and Territorial Health Officials, the National Association of County and City Health Officials, the Association of Public Health Laboratories, the Council of State and Territorial Epidemiologists, and the National Public Health Information Coalition. In addition, feedback also was incorporated from departments and agencies across the U.S. government.

Novel Influenza A Virus Pandemic Intervals

The novel influenza A virus pandemic intervals are based on what is known about past influenza transmission and on experience from recent events (e.g., 2009 H1N1 pandemic, H3N2v in the United States, H7N9 in China, and continuing sporadic human cases of H5N1).Typically, epidemic curves are used to monitor an outbreak as it is occurring, describe the outbreak retrospectively, and document the timing of interventions relative to the acceleration and deceleration of the outbreak. Modeled epidemic or pandemic curves also can be used to describe potential events over time. Using these models for forecasting purposes might be particularly valuable for anticipating conditions and identifying actions that might flatten or otherwise attenuate the epidemic or pandemic curve.

For the purposes of responding to novel influenza viruses and potential pandemics, the six intervals (investigation, recognition, initiation, acceleration, deceleration, and preparation) represent events that occur along a hypothetical pandemic curve (Figure). Pandemic curves differ by duration and intensity depending on many factors, including the geographic area in which they occur, the season of their emergence, and related population dynamics. The WHO pandemic influenza phases, which can be used to describe and communicate worldwide disease progression, provide a general view of the emerging epidemiologic situation essentially by aggregating epidemic curves from around the world. The CDC intervals serve as additional points of reference to provide a common orientation and clearer epidemiologic picture of what is taking place and when to intervene. The intervals are flexible enough to accommodate the likely asynchrony of pandemic progression in different areas to allow for local, state, and federal actions appropriate to jurisdiction-specific conditions (e.g., a jurisdiction with cases versus a jurisdiction with no cases but that is close to an area with cases). State and local health authorities might even elect to implement interventions asynchronously within their jurisdictions by focusing early efforts on communities that are first affected. The state/local initiation, acceleration, deceleration, and preparation indicators can be asynchronous to the federal indicators (Appendix).

For state and local planning, the intervals describe the progression of the pandemic within communities and provide a detailed framework for defining when to respond with various actions and interventions at any point in a pandemic. These actions should be proportionate to the transmissibility and severity of the emerging virus. The intervals are further stratified into eight domains so that the trajectory of planning and response activities for any one domain can be more easily followed. The eight domains are incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination. The intervals also might be valuable as a common reference point because they can be used to link the status of a pandemic with specific interventions.

U.S. experiences during recent novel influenza events were useful for testing the concepts in the proposed intervals and the decisions and actions that were implemented during those intervals. The public health impact of novel influenza virus strains can differ substantially, both in geographic spread and mortality. For example, the 2009 H1N1 outbreak was caused by a highly transmissible novel influenza virus that emerged in North America and resulted in a pandemic (2), whereas the H3N2v virus, which also emerged in North America, caused approximately 300 cases in humans and limited outbreaks involving domestic animal-to-human transmission (3). The H7N9 outbreak was caused by a novel influenza virus that emerged outside of U.S. borders and had high mortality but has not spread to other countries thus far (5). These experiences have provided opportunities to test the validity and usefulness of the intervals and the recommendations for public health actions triggered by each interval to ensure that they are applicable in a diverse range of scenarios.

Pandemic Interval Definitions

To define the intervals, the relationship between the timing of the broad WHO phases and the more detailed planning intervals was examined (Figure). In addition to the relationship to the WHO phases, the intervals are characterized by specific transmission-related indicators (Table) and by the types of response activities that should occur within each interval (Appendix).

Progression through the intervals is not exclusively linear. For example, identification of a novel influenza A virus does not necessitate progression to the next interval (the recognition interval) if the virus does not demonstrate the potential for ongoing transmission. Similarly, after the preparation interval, subsequent waves of outbreaks will prompt federal, state, and local public health officials to reenter the acceleration, deceleration, and preparation intervals. The duration of each pandemic interval might vary from weeks to months depending on the characteristics of the virus and the public health response.

Investigation Interval: Investigation of Novel Influenza Cases

The investigation interval is initiated by the identification and investigation of a novel influenza A infection in humans or animals anywhere in the world that is judged by subject-matter experts to have potential implications for human health (Appendix [Table 1]). Public health actions focus on targeted surveillance and epidemiologic investigations to identify human infections and assess the potential for the virus to cause severe disease in humans, including person-to-person transmission, co-investigations of animal outbreaks with animal health representatives, and consideration of case-based control measures (i.e., antiviral treatment and antiviral postexposure prophylaxis of contacts for infected humans and isolation of humans and animals who are infected). After recognition of a case of novel influenza infection in a human, as occurred with the H7N9 and H3N2v viruses, animal investigations subsequently identified circulation of influenza viruses in birds and swine, respectively, and identified the reservoir of these previously unrecognized novel influenza viruses. CDC conducts an IRAT assessment during the investigation interval to characterize the potential for emergence, and if the virus does emerge, the severity of human infection (12). Generally, identification of human cases of novel influenza A infection are reported to WHO in accordance with the International Health Regulations (15).

Recognition Interval:
Recognition of Increased Potential for Ongoing Transmission

The recognition interval is initiated when increasing numbers of human cases or clusters of novel influenza A infection are identified anywhere in the world, and the virus characteristics indicate an increased potential for ongoing human-to-human transmission (Appendix [Table 2]). Public health actions concentrate on control of the outbreak, with a focus on potential use of case-based control measures, including treatment and isolation of ill persons and voluntary quarantine of contacts.

Initiation Interval: Initiation of the Pandemic Wave

The initiation interval begins when human cases of a pandemic influenza virus infection are confirmed anywhere in the world with demonstrated efficient and sustained human-to-human transmission (Appendix [Table 3]). The definition of efficient and sustained transmission is established during an event based on the epidemiologic characteristics of the emerging virus. For example, efficient transmission could be defined as a household or an institutional attack rate of ≥20% in more than two communities, and sustained could be defined as transmission of virus for three or more generations in more than one cluster. Continued implementation of case-based control measures and routine personal protective measures (e.g., hand hygiene) is essential, as is enhanced surveillance for detecting additional cases of the novel virus to determine when community mitigation measures will be implemented. If possible, PSAF results (13) should be used to ensure that actions are proportional to the severity of the disease caused by the virus.

Acceleration Interval: Acceleration of the Pandemic Wave

The acceleration interval is indicated by a consistently increasing rate of pandemic influenza cases identified in the United States, indicating established transmission (Appendix [Table 4]). Consideration of immediate initiation of appropriate community mitigation measures such as school and child-care facility closures and social distancing (16) in addition to the efficient management of public health resources (including medical countermeasures and vaccines, if available) are of primary importance in this interval (17) and are guided by PSAF results. Isolation and treatment of ill persons and voluntary quarantine of contacts continue as key mitigation measures. Historical analyses and mathematical modeling indicate that early institution of combined, concurrent community mitigation measures might maximize reduction of disease transmission and subsequent mortality in the affected areas (18–21).

Deceleration Interval: Deceleration of the Pandemic Wave

The deceleration interval is indicated by a consistently decreasing rate of pandemic influenza cases in the United States (Appendix [Table 5]). During this interval, planning for appropriate suspension of community mitigation measures and recovery begins. State or local health officials might rescind community mitigation measures in certain regions within their jurisdiction when no new cases are occurring or are occurring infrequently.

Preparation Interval: Preparation for a Subsequent Pandemic Wave

The preparation interval is characterized by low pandemic influenza activity, although outbreaks might continue to occur in certain jurisdictions (Appendix [Table 6]). Primary actions focus on discontinuing community mitigation measures; facilitating the recovery of the public health, health-care, and community infrastructure; resuming enhanced surveillance protocols to detect subsequent waves; evaluating the response to the initial wave; and preparing for potential additional waves of infection. Because this interval can last from weeks to months, planning and preparation for a subsequent pandemic wave should reflect this variability. A pandemic is declared ended when evidence indicates that influenza, worldwide, is transitioning to seasonal patterns of transmission (8). Like the 2009 H1N1 strain, pandemic strains might circulate for years after the pandemic, gradually taking on the behavior and transmission patterns of seasonal influenza viruses.

Assessing Risks to Enhance Decision-Making

In addition to describing the progression of a pandemic, certain assessments, interpretations, and findings (i.e., indicators) are used to define the transition points between the intervals (Table). Within each interval, certain actions can be determined for state, local, and federal governments. Each indicator also initiates a set of important decisions that affect actions in the current and subsequent intervals. These decisions can range from formal generation and analysis of options to more informal but equally important discussions among subject-matter experts, pandemic response leaders, and various stakeholders (Appendix).

Decisions about appropriate actions require information regarding the real or potential impact of the novel virus on public health. Within any interval, decisions about which actions should be considered should take into account numerous factors, such as virus transmission parameters, severity of disease among different age and risk groups, availability and effectiveness of control measures and treatment options (e.g., community interventions, antivirals, and vaccines), and impact on health care, schools, businesses, and the community.

Although data needed to make decisions might be limited during the earliest intervals, delaying action might weaken the effectiveness of the response. Therefore, estimating the likelihood of risks, particularly the risks of transmissibility, severity, and antiviral resistance, is critical (12,13,22). In addition, certain actions, such as the decision to produce a pandemic vaccine, require extensive preparation or time to implement, mandating that decision-making be initiated and completed as early as possible before the intervals when those actions need to occur and usually long before adequate data are available to support the need for those actions with certainty.

CDC developed two risk assessment tools for the decision-making framework, IRAT (12) and PSAF (13). Both are designed to be used during the initial intervals when data are limited, to allow for iterative updates as new information becomes available and to accommodate various potential scenarios. Once completed, results of both tools are communicated to federal, state, and local decision-makers to guide public health actions (Appendix).

Influenza Risk Assessment Tool

When a novel influenza A virus is identified in humans but is not circulating widely in the human population, it is important to evaluate 1) the risk that the virus will develop efficient and sustained human-to-human transmission and 2) the risk that the virus will substantially affect public health. IRAT was developed to facilitate such an assessment (12). Therefore, the indicator for the investigation interval, which is a newly identified influenza A virus in animals or identification of a novel influenza A virus recovered from humans, can serve as an initial trigger to conduct IRAT scoring.

IRAT is used by the U.S. government and the WHO Global Influenza Surveillance and Response System as a risk assessment process that involves data gathering, discussion, and consensus building among subject-matter experts to assign a risk score. Ten predefined risk elements are given a risk score. These 10 elements fall into three categories: 1) attributes that pertain to the biologic properties of the virus (four elements), 2) attributes of the population (three elements), and 3) attributes of the ecology and epidemiology of the virus (three elements) (12). A team of experts assigned to each particular element provides a risk score for the virus for that element. A weight is then applied to the element scores for each of the two risk questions (i.e., emergence and impact). The results of this process can be used to decide whether and how to act and communicate concerns regarding both emergence and potential public health impact. As new information becomes available, the scoring can be repeated. This process has been used to assess recently emerging viruses such as H3N2v and H7N9 for vaccine development, manufacturing, and stockpile decisions. After a novel virus has achieved efficient and sustained transmission, PSAF can then be used to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences.

Pandemic Severity Assessment Framework

Once a novel influenza virus has emerged and is circulating in human populations, the risk posed by the pandemic can be assessed. In 2007, as part of the interim guidance for community mitigation strategies, the Pandemic Severity Index was introduced as a tool to define the severity of a future influenza pandemic. To facilitate risk communication, the index had five categories similar to the hurricane severity scale, ranging in severity from category 1 (moderate severity) to category 5 (most severe) and was based on a hypothetical 30% attack rate and ranges of case-fatality ratios associated with a particular novel influenza virus (16). Experiences from the 2009 H1N1 pandemic identified that early data on the less severe but highly transmissible characteristics of the virus in the community were limited. Consequently, the Pandemic Severity Index, which based severity solely on mortality, tended to overestimate severity because more severe cases are likely to be reported at the initiation of a pandemic. Building on those lessons, PSAF was developed to characterize the potential impact of a pandemic relative to previous influenza epidemic and pandemic experiences (13). PSAF can be used early in a pandemic and assessments can be repeated as information changes. Although IRAT focuses on risk of emergence and potential for impact if emergence occurs, PSAF focuses on epidemiologic parameters of transmissibility and severity after a virus has emerged with efficient and sustained transmission and requires a sufficient number of cases and clusters in humans to allow for the assessment to be completed. Depending on the number of cases, size of clusters, and the geographic location of outbreaks, the trigger for using PSAF might be as early in the pandemic as the recognition interval but is more likely to be triggered during the initiation interval and regularly updated as the pandemic progresses.

PSAF is based on transmissibility and clinical severity parameters and uses different scales for initial assessments in an emerging pandemic, and for later, more refined assessments. The initial assessment, performed early in the outbreak when epidemiologic data are limited, uses a dichotomous scale of low-moderate versus moderate-high transmissibility and severity. The later assessment, performed when more reliable data are available, is more refined, using a 5-point scale for transmissibility and a 7-point scale for clinical severity. After available data are assessed on these scales, the overall results are plotted with the measures of transmissibility along a y-axis and the measures of severity along an x-axis and compared with referent points such as previous pandemics or particularly severe influenza seasons (13). In the very early stages of an emerging pandemic, public health officials reiterate the importance of early treatment of ill persons as well as community mitigation measures to slow the spread of influenza, including voluntary isolation (i.e., ill persons staying home when sick), respiratory etiquette, hand hygiene, and guidance on treatment with antivirals. The results of PSAF assessments help national, state, and local decision-makers determine whether to implement additional community mitigation measures, including those that can be very disruptive and might have a more serious economic and societal impact on individual persons and communities (e.g., school dismissals or quarantine of contacts).

Using the Intervals, Influenza Risk Assessment Tool, and Pandemic Severity Assessment Framework

The use of transmission-defined intervals and tools such as IRAT and PSAF to assess risks and potential impact provides information that can guide decision-making and actions across different jurisdictions and levels of government and help inform appropriate risk communication strategies. A list of some of the key decisions and options for action that are triggered by progression through each interval are described (Appendix). Planning and response efforts for recent novel influenza A viruses and pandemics have been organized into eight domains to ensure that subject-matter expertise is properly applied to all aspects of the event. The decisions and actions are further stratified into these domains so that the trajectory of planning and response activities for any one domain can be more easily followed. The eight domains are incident management, surveillance and epidemiology, laboratory, community mitigation, medical care and countermeasures, vaccine, risk communications, and state/local coordination. The tables are not meant to be prescriptive or comprehensive but rather to identify numerous priority issues that need to be addressed during each interval. The circumstances of each situation dictate the timing of decisions and actions.

Discussion

The updated influenza pandemic framework provides six intervals and indicators for public health decision-making and actions during the progression of a novel influenza A virus from emergence through pandemic. The intervals are based on events that occur along a hypothetical epidemic curve. Although the actual shape of a future epidemic curve cannot be accurately predicted and might be modified by interventions, the use of an idealized curve permits generally applicable intervals to be defined. The concept of describing intervals of a pandemic can be applied to a single outbreak occurring in an individual state or a community, or information from multiple outbreaks can be aggregated to describe the situation at the national level.

Because the resources and demographics among different regions and states in the United States vary widely, defining detailed indicators that address every potential situation is impossible. Certain indicators might not be scalable to all levels of government, and others do not have corresponding actions from every participant group. However, the proposed intervals, triggers for decision-making, and actions are meant to be flexible enough to allow for the implementation of local, state, and federal actions appropriate to jurisdiction-specific conditions.

This framework is designed to assist with decision-making but does not diminish or replace the role of scientific expertise, particularly as a novel influenza outbreak unfolds. An effective pandemic response is based on numerous assumptions and actions that must be continuously reassessed with accumulated data as the pandemic progresses. The content of this framework is intended to support and organize planning and response efforts at the federal, state, and local levels. The use of common concepts is critical for tracking the course of the pandemic, for communication, and for implementing timely, coordinated response efforts.

Acknowledgments

This report is based, in part, on contributions by subject-matter experts who represented professional societies, including the Association of State and Territorial Health Officials, the National Association of County and City Health Officials, the Association of Public Health Laboratories, the Council of State and Territorial Epidemiologists, and the National Public Health Information Coalition, as well as federal agencies including the U.S. Department of Health and Human Services, the Food and Drug Administration, the National Institutes of Health, the Biomedical Advanced Research and Development Authority, and CDC.

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