Emerging Infectious Diseases: Actions Needed to Ensure Improved Response to Zika Virus Disease Outbreaks
Published: 2017-05-23T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Zika virus disease can cause adverse health outcomes. This statement summarizes the findings of GAO’s May 2017 report that is being released concurrently on progress made and challenges faced by federal agencies in responding to the Zika virus outbreak in the United States.
GAO examined (1) information on what is known and not known about the epidemiology of the Zika virus and challenges with conducting surveillance and epidemiological studies, (2) characteristics of different authorized diagnostic tests, challenges test manufacturers and users faced, and the extent to which FDA and CDC followed their own communication guidance, and (3) the strengths and limitations of available mosquito control methods, and challenges federal agencies faced.
GAO reviewed documents and interviewed officials about the Zika virus response. GAO also convened an expert meeting with the assistance of the National Academy of Sciences to discuss various issues related to Zika virus.
section_title: What GAO Found
paragraphs: Since Zika virus disease was a newly emerging disease threat in the United States, the Centers for Disease Control and Prevention (CDC), and the states were not fully equipped with needed information and resources at the beginning of the outbreak. This presented several challenges for surveillance and research efforts, such as establishing a national definition for reporting cases. Knowledge about Zika virus epidemiology has increased in the past year, for example, its associated adverse health outcomes, and various modes of transmission. Most of the 5,197 Zika virus disease cases reported by April 5, 2017 across 49 states in the United States were associated with travel to affected areas outside the continental United States; only two states—Florida and Texas—reported local mosquito-borne transmission—216 were in Florida and 6 in Texas. The vast majority of the 36,504 cases reported in U.S. territories have been acquired through presumed local, mosquito-borne transmission in Puerto Rico. While much has been learned about the epidemiology of the Zika virus, many unknowns remain, including the actual number of infections in the United States and the full spectrum of short-term and long-term outcomes.
The 16 Zika virus diagnostic tests authorized during the outbreak varied in their performance and operational characteristics. For example, they varied in their ability to detect the virus and provide accurate results. In developing the diagnostic tests, manufacturers faced challenges in several areas, including access to clinical samples and other authorized diagnostic tests for comparison purposes. Users of the tests also encountered challenges, including determining the most accurate test to use, having access to different tests, and obtaining equipment needed to conduct the tests. Some manufacturers raised concerns about the difficulty in developing diagnostic tests that met the Food and Drug Administration’s (FDA) requirements for Emergency Use Authorization and some users expressed concerns about selecting tests amongst those authorized. GAO also determined that CDC and FDA did not consistently communicate sufficient information about diagnostic tests, including providing clear information that would have enabled users to more easily compare performance across different tests.
Mosquito control programs in the United States are implemented at state and local levels and are critical to mitigating the risks associated with the Zika virus. Control methods include applying pesticides, reducing available water sources for breeding, and using personal protection. Each method has its strengths and limitations. For example, some control methods are more effective at reducing mosquito populations while others help prevent individuals from mosquito bites. Similarly, each method has some limitations, for example, there is varied public opposition to the use of certain pesticides. CDC supports state and local mosquito control activities primarily by providing guidance on mosquito control methods and funding to support certain mosquito control efforts. Challenges federal agencies identified in supporting these activities include sustaining staff expertise in mosquito control during periods when there are no outbreaks, funding constraints, and effectively communicating information about the geographical distribution of mosquitoes that transmit the Zika virus.
section_title: What GAO Recommends
paragraphs: In its May report GAO made five recommendations to FDA and CDC, including that CDC establish a transparent process for providing test manufacturers access to diagnostic tests for comparison purposes and FDA and CDC provide information to help ensure that users of diagnostic tests can compare performance. The agencies agreed with four recommendations and partially with the fifth and identified actions to implement them.

section_title: Letter
paragraphs: Thank you for the opportunity to discuss our work on the federal response  to Zika virus disease outbreaks, with particular focus on epidemiology,  diagnostic tests, and mosquito control. Emerging infectious diseases,  such as Zika virus disease, are an ongoing threat to the health and  livelihoods of people and animals worldwide. Despite many advances in  medical research and treatments during the past century, infectious  diseases are still a leading cause of death worldwide. Our testimony  today summarizes our report entitled Emerging Infectious Diseases:  Actions Needed to Address the Challenges of Responding to Zika Virus  Disease Outbreaks which is being released today. We have also issued  several other reports on infectious diseases.
Zika virus disease is caused by the Zika virus, which is spread to people  primarily through the bite of an infected mosquito (Aedes aegypti). Many  people with Zika virus infection will not have any signs or symptoms or  will have only mild symptoms. The Zika virus attracted attention from  health officials in the United States and abroad after associations were  suspected between increases in reported cases of Zika virus infection  and reported cases of microcephaly in newborns and other neurological  syndromes in Brazil in 2015.
Several U.S. federal agencies are involved in the response to Zika virus  disease outbreaks. Specifically, the Centers for Disease Control and  Prevention (CDC) collects data from states on reported cases of  nationally notifiable diseases through surveillance systems. The Food and  Drug Administration (FDA) oversees the safety and effectiveness of  diagnostic tests. The Secretary of Health and Human Services (HHS) can  make a declaration of emergency that can allow FDA to issue Emergency  Use Authorization (EUA) of medical products to be used when adequate,  approved, and available alternatives are lacking. FDA’s website includes  a current list of available diagnostic tests and associated information  about each test. FDA has authorized two different types of diagnostic  tests for the Zika virus—molecular and serologic.
Our May 2017 report and my statement today address (1) what is known  and not known about the epidemiology of the Zika virus, and challenges  in conducting surveillance and epidemiological studies, (2) characteristics  of different Zika virus authorized diagnostic tests, challenges  manufacturers and users of diagnostic tests have faced, and the extent to  which CDC and FDA followed their own communication guidance  concerning diagnostic tests during the recent U.S. outbreak, and (3)  available mosquito control methods, their strengths and weaknesses, and  challenges federal agencies face in assisting mosquito control efforts.
For our May 2017 report, we reviewed agency documents including  reports on Zika virus epidemiology, diagnostic testing guidance, agency  documents on mosquito control, and information on all authorized  diagnostic tests for Zika virus disease. We also interviewed the  manufacturers of authorized tests, officials from key federal agencies and  departments, selected state and local public health entities, and public  health organizations responding to the domestic Zika virus outbreak. We  also convened, with the assistance of the National Academy of Sciences,  a meeting with 16 experts from federal and state governments, academia,  and industry who combined knowledge of Zika virus epidemiology,  diagnostic testing, and mosquito control, to identify and discuss  experiences and challenges that arose during the Zika virus outbreak  response. Additional information on our scope and methodology is  available in our report. We performed the work on which this testimony is  based in accordance with generally accepted government auditing  standards.
subsections: section_title: Challenges to Gathering New Information about Zika Virus Epidemiology
paragraphs: Surveillance and research conducted during the recent Zika virus disease  outbreaks around the world have established some new knowledge about  the epidemiology of the Zika virus, including information about the  incidence of the disease and the distribution of cases, and its associated  adverse health outcomes. Most of the 5,197 Zika virus disease cases  reported by April 5, 2017 across 49 states in the United States were  associated with travel to affected areas outside the continental United  States; only two states—Florida and Texas—reported local mosquito- borne transmission—216 were in Florida and 6 in Texas. Most of the  36,504 cases reported in U.S. territories have been acquired through  presumed local, mosquito-borne transmission in Puerto Rico. According  to the World Health Organization (WHO) and CDC, there is now evidence  that the Zika virus causes microcephaly, brain abnormalities, and other  birth defects and neurological disorders, based on the totality of evidence  from current epidemiological and clinical studies.
Nevertheless, many unknowns about the Zika virus remain, including (1)  the total number of people with symptomatic and asymptomatic  infections, (2) the biological mechanisms, risks, reasons for geographic  differences, and the full spectrum of outcomes associated with maternal- fetal transmission, (3) the presence and duration of the virus in different  bodily fluids, and (4) the role of prior exposure to Zika and other closely  related viruses in risk and severity of Zika virus disease outbreaks, and  (5) the full spectrum of outcomes associated with Zika virus infection.
When the outbreak started in the United States, CDC, and state and local  public health agencies, and public health organizations, faced some  challenges in establishing and implementing surveillance systems for Zika  virus disease and infection and its associated health outcomes.  Challenges included establishing surveillance case definitions early in the  outbreak when little was known about the Zika virus, timely  communication of critical information that was rapidly evolving, and the  lack of interoperability between surveillance systems. We also identified  two key challenges for epidemiological research: (1) time and resources  required for studies needed to establish association and causality  between the Zika virus and associated health outcomes and (2)  insufficient data and models for predicting the spread of the Zika virus.
section_title: Characteristics of Different Diagnostic Tests Varied, Manufacturers and Users Faced Several Challenges, and FDA and CDC Did Not Consistently Communicate Sufficient Information
paragraphs: By April 12, 2017, FDA had authorized 16 diagnostic tests for the Zika  virus under EUAs, following a public health emergency declaration. In  response to the Zika virus outbreak, CDC manufactured and received  EUA from FDA for both molecular and serologic tests. We found that  authorized diagnostic tests used for the recent Zika virus outbreak varied  in their performance and operational characteristics. Molecular and  serologic tests have different strengths and limitations, but some of the  limitations can be mitigated by using the CDC algorithm.
It is important to recognize that a negative molecular test does not rule  out Zika virus infection because the amount of virus in the sample could  be too low to be detected at the time of molecular testing. Some scientists  expressed concern over the limit of detection for the Zika virus by some  authorized molecular diagnostic tests, which could have resulted in  molecular testing missing Zika infections. CDC provided guidance  intended to reduce the risk of inaccurate results by recommending that  molecular tests should be further tested with a serological test. One  critical issue with serological Zika virus disease testing is potential cross- reactivity – when antibodies to similar viruses react. For example, cross- reactions occur in the diagnostic tests for Zika and dengue because these  viruses are closely related.
We identified challenges that manufacturers of diagnostic tests for Zika  virus faced including: (1) lack of knowledge of biological aspects of the  virus and immune response, (2) difficulty in accessing well-characterized  clinical samples, (3) getting access to EUA tests for use as a comparator  test, and (4) gaining cooperation with international entities.
The first challenge manufacturers faced was uncertainty at the beginning  of the outbreak about which sample type to use for molecular testing. For  instance, the Zika virus had been found to be present longer in urine than  in blood, but information on how long the virus could persist in different  bodily fluids was still evolving making it difficult to develop diagnostic  tests.
Second, during the early stages of the outbreak there was a lack of well- characterized clinical samples for Zika virus diagnostic test development.  Several manufacturers told us that there were insufficient quantities of  available samples, and samples that were available were expensive.
Third, FDA recommends that manufacturers perform clinical evaluation  studies that compare their new tests to another “comparator” assay  (test). Similarly, a CDC document states that CDC should provide a  consistent, fair, and transparent review process for all public-private  initiatives, even during emergencies. According to CDC officials, the CDC  developed EUA tests were not made available to some commercial  manufacturers for use as comparator tests because these tests are  distributed only to public health laboratories performing Zika virus clinical  diagnoses. Moreover, according to CDC officials, in the early stage of the  response CDC did not have the capacity to both adequately support  public health laboratories and also supply commercial manufacturers with  these tests. Ultimately, CDC distributed its tests to four manufacturers  through technology transfers and we found that 2 of the 12 authorized  molecular diagnostic test labels listed CDC’s test as their comparator test.  However, one manufacturer told us their request to CDC for reagents to  perform the CDC test as a comparator test was denied because they  were a commercial manufacturer. CDC officials we spoke with were  unclear of how the process to transfer authorized CDC tests to  manufacturers originally started. Standards for Internal Control in the  Federal Government state that agencies should document their  operational processes to ensure that the organization meets its  objectives. Without a clear and transparent process for distributing CDC  diagnostic tests, CDC may not be able to support the development of  capacity in the commercial sector to meet the needs during an outbreak.
Fourth, interacting with international entities to obtain samples and  perform testing presented challenges for manufacturers. For instance,  foreign countries have different laws that must be followed. A  manufacturer we interviewed tried to bring equipment to perform a  diagnostic test into another country for testing but it faced challenges  getting the necessary import license.
We also found that some diagnostic test users faced challenges  complying with equipment requirements to perform tests as specified in  the EUA labels, and determining the most accurate test. Moreover,  although CDC officials told us that all states had at least one public health  laboratory that had the equipment to run a CDC test, representatives from  several laboratories we interviewed told us they had to acquire specific  new specialized equipment to be able to perform a certain EUA  diagnostic test.
An FDA document states that the agency should share information that is  up-to-date, understandable, and easily accessible so diagnostic test  users have some basis for choosing which medical products to purchase  and use. We found that although performance characteristics are listed  on individual diagnostic test labels, they are not available in a  consolidated format. According to FDA officials, the agency began  collecting information using reference samples because different  manufacturers were using different types of samples and potentially  different methods to determine the limit of detection of their tests. Until  limit of detection data have been extracted and summarized from all the  diagnostic test labels, it may be difficult and time-consuming for users to  compare the performance characteristics and results of diagnostic tests.
Another challenge users faced was that without knowing the identity of  the comparator test, it was more difficult for them to compare  performance characteristics across different diagnostic tests and  determine the most appropriate test for them to use. Experts at our  meeting agreed that identifying the comparator test would make it easier  to compare the risks and benefits of different Zika virus diagnostic tests.  An FDA document recommends a clear description of all methods used  and how and what data were collected when performing comparison  testing, including a description of the comparator test. When we  compared product labels for different molecular tests, we found that while  labels listed the type of test used for comparison, 6 of 12 product labels  did not list the identity of the test used for comparison. FDA officials  stated that the comparator test for authorized diagnostic tests can either  be another authorized test or a validated reference method, and that  manufacturers are not required to identify the comparator test used. FDA  staff told us they are concerned that labels identifying comparator tests  could be used to make inappropriate claims or be misinterpreted by end  users.
Standards for Internal Control in the Federal Government state that  agencies are to communicate quality information externally through  reporting lines so that external parties can help an entity achieve its  objectives and address related risks.  CDC did not make publically  available data comparing the performance characteristics of different  CDC diagnostic tests that it distributed during the outbreak.  CDC’s  website has information about the performance of its two authorized  diagnostic tests but not the laboratory developed test it distributed.  According to a HHS report, CDC did not provide information about one of  its diagnostic tests because it could potentially create confusion and could  have caused public health laboratories to discontinue use of an EUA test,  and it had not done a comprehensive comparison of the two tests.  Because CDC did not publicly provide performance information about its  laboratory developed test—which was distributed to some public health  laboratories—questions arose regarding the sensitivity of the two CDC  tests.
Representatives of three scientific professional societies told us that  information about the development and verification of CDC’s diagnostic  tests should be made available to the scientific and medical communities.  Access to such data would provide transparency and allow for optimal  patient care, according to these representatives. According to these  scientific professional societies’ representatives, the lack of access to  data regarding test performance prevented laboratory professionals from  making informed decisions about which test to adopt or recommend  during the outbreak. Without including information on the performance  characteristics of tests it is distributing, CDC cannot ensure that  healthcare providers and the public have the information they need to  make informed decisions about which test is best for their use.
In our May 2017 report we recommend that FDA consolidate information  from individual diagnostic test labels and make it available in a form that  enables diagnostic test users to more readily compare information across  tests and require manufacturers of diagnostic tests to list the identity of  comparator tests on their labels. We also recommend that CDC establish  a transparent process to provide CDC diagnostic tests, on request, to  manufacturers that are in the final stages of diagnostic test authorization,  and include information on CDC-developed tests, including laboratory  developed tests. HHS agreed with our recommendations for FDA to  consolidate information about tests, require manufacturers to list the  identity of the comparator assay, and that CDC establish a transparent  process for distributing CDC-developed tests. In response to our  recommendation to include information on CDC-developed tests  distributed to public health laboratories, HHS partially concurred and  provided clarifying information. HHS agreed that it should share  information on CDC-developed tests that have received EUA. However,  regarding this recommendation, HHS did not agree with our  recommendation that it should share information on CDC’s laboratory- developed tests that have not received EUA because CDC is unable to  provide detailed information on characteristics of these unstandardized  tests. We maintain that sharing information about these laboratory  developed tests that are used for comparison testing is important  because of the concerns that were raised regarding the sensitivity of one  of CDC’s EUA tests. We recognize that laboratory-developed tests that  have not received EUA are not standardized, but we believe that CDC  can provide certain information on the performance characteristics and  quality of these tests based on its knowledge about these tests. Sharing  this information could help other diagnostic test users make informed  decisions about which test to adopt or recommend. HHS also noted that  CDC does not distribute laboratory developed tests that have not  received EUA but shares them with public health laboratories. In  response to this comment, we modified our recommendation to reflect  this information.
section_title: Mosquito Control Methods Have Strengths and Limitations, and Federal Agencies Are Challenged in Assisting These Efforts
paragraphs: Different types of mosquito control methods are available in the United  States and each has strengths and limitations. The methods can be  combined with surveillance of the mosquito population, using an  integrated approach (i.e., pesticide use, traps, public education programs,  and others) to optimize the application of multiple control methods,  depending on knowledge of mosquito biology and distribution.
Because Zika virus disease is not yet preventable by known drugs or  vaccines, mosquito control is critical in mitigating risks associated with  this disease. Mosquito control in the United States is implemented and  overseen by state and local entities such as mosquito control districts and  health agencies. CDC, through sources including the American Mosquito  Control Association, identified over 900 entities in the United States that  perform mosquito control; however, not all geographic areas in the United  States are covered. Federal agencies may support such control entities  with funding, subject matter expertise, and may regulate some control  methods such as pesticides.
The federal government has a limited and indirect role in supporting  mosquito control efforts, which are mainly implemented at the state and  local levels. According to CDC documentation, the agency developed  technical guidance and provided funding and technical assistance to  support state and local mosquito control activities. We identified four  challenges the federal government faced in supporting these mosquito  control efforts during the Zika virus outbreaks: (1) timing of the availability  of resources and sustaining expertise, (2) communicating information  about current mosquito distribution, (3) linking the effects of mosquito  control to disease outcomes, and (4) having limited information about  mosquito control entities.
Federal agencies faced challenges related to the cyclic nature of  mosquito-borne diseases, including recruiting and maintaining expertise.  According to CDC, when the disease fades, the jobs and resources also  go away, so that the next time the disease appears, staff must be  retrained or new staff trained. CDC officials also told us that mosquito  control needs vary with seasonal cycles, resulting in periods of several  months that require more resources followed by some periods when little  or no resources are needed.
CDC also faced challenges in communicating the presence of mosquitoes  in a manner that was clear and useful to different groups, such as  mosquito control entities and the general public. CDC distributed maps of  the estimated potential range of the primary Zika virus mosquito vectors  on its webpages and in guidance, but imprecision in the maps can lead to  confusion, according to some mosquito control officials. According to  CDC officials, the maps allowed states to determine the level of effort  needed for more precise mosquito surveillance as well as to show the  public where they may encounter certain mosquito species. One  mosquito control official told us of confusion about CDC’s maps resulting  from people failing to look at the qualifications stated in the map captions  and mistakenly concluding that an entire state was infested with Zika  virus vector mosquitoes. Further, detailed information about how the  maps were created, including data sources and assumptions, was not  posted on the CDC website or in documentation associated with the map.  According to Standards for Internal Control in the Federal Government,  management should use quality information to achieve the agency’s  objectives and should select appropriate methods to communicate  externally the necessary quality information to achieve those objectives.  This includes selecting appropriate methods to communicate externally,  considering factors such as the intended recipients and the nature of the  information being communicated.
Regarding information presented on CDC maps, experts we interviewed  suggested including more details, such as collection records, measures of  the stability of the mosquito populations, and areas of risk for  transmission of mosquito-borne diseases. Without such context, CDC’s  maps could generate confusion about mosquito presence, resulting in  concern among residents and public relations challenges, among other  things. In our report we recommended that CDC provide details such as  collection records, dates, and data limitations on posted and  disseminated mosquito distribution maps to better inform mosquito control  experts and the general public. HHS agreed with this recommendation.
CDC faced challenges in determining whether mosquito control efforts  are associated with the reduction of mosquito-borne disease. For  example, mosquito control entity officials told us that the entities’  mosquito control efforts are not directly linked to disease reduction. Other  challenges to analyzing the relationships between mosquito control  methods and disease reduction include the dependence of transmission  on factors such as weather, human susceptibility, and immunity.
CDC’s capacity to develop a national strategy for mosquito control  depends on its knowledge of mosquito control entities and their  capabilities. We found that CDC relied on external sources to compile a  list of mosquito control entities. CDC staff told us this list is likely to  capture the larger, well-funded entities but may miss some smaller ones.  Further, mosquito control capabilities in the United States vary by  geographic area. A mosquito control official we interviewed agreed that  variability in mosquito control entity capacities is significant. This  variability makes it more challenging for CDC to determine the status of  mosquito control efforts in different regions of the United States and to  identify regions that may need technical guidance or assistance.
In conclusion, federal agencies can provide important information that can  help users compare diagnostic tests and assist mosquito control efforts  implemented at the state and local levels. Information on performance  characteristics presented in each diagnostic test product label was not  consolidated across available tests, were not consistently reported for  diagnostic tests, and the identity of the comparator test was not listed on  some labels, making it difficult for users to make informed decisions about  which test to use or recommend to patients. The information that CDC  included in its maps did not include sufficient details about its estimates of  potential distribution of mosquitoes that can carry the Zika virus, which  made it difficult for mosquito control experts and the public to correctly  interpret and use such data.
CDC developed the first two authorized diagnostic tests for the Zika virus  and offers these tests to public health laboratories but not to some  manufacturers. Such manufacturers additionally encountered difficulty  acquiring authorized tests from other manufacturers. Without a clear and  transparent process for distributing CDC-developed diagnostic tests to  manufacturers, the agency may not be able to develop the capacity of the  commercial sector to be able to meet the needs during an outbreak.
Chairman Murphy, Ranking Member DeGette, and Members of the  Subcommittee, this concludes my prepared statement. I would be happy  to respond to any questions you may have.
For questions about this statement, please contact Timothy M. Persons,  Ph.D., Chief Scientist, at (202) 512-6412 or personst@gao.gov. Contact  points for our Offices of Congressional Relations and Public Affairs may  be found on the last page of this statement. Individuals making key  contributions to this statement include Sushil Sharma, Ph.D, Dr.PH,  (Assistant Director), Ashley Grant, Ph.D, MPH, Hayden Huang, Ph.D.,  Amber Sinclair, Ph.D., and Penny Pickett, Ph.D.
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