GAO Faults U.S. Handling of Zika Outbreak; IDs Challenges to Test Development

The US. Government Accountability Office (GAO) found that the U.S. Department of Health and Human Services was “reactive” in its handling of the Zika virus outbreak including in its preparedness, detection capabilities, and response. The GAO highlighted how this lack of preparedness resulted in challenges felt by both test developers and test users throughout test development, some which remain today.

Specifically, the GAO says, diagnostics manufacturers encountered obstacles throughout the development process, including a lack of access to clinical samples and other diagnostic tests for comparison purposes. Additionally, test users faced challenges, in determining the most appropriate test to use, accessing different tests, and obtaining the equipment needed to conduct the tests. Concerns remain regarding the accuracy of the diagnostic tests and CDC’s guidance for testing procedures. In its final report, Emerging Infectious Diseases: Actions Needed to Address the Challenges of Responding the Zika Virus Disease Outbreaks, released on May 23, the GAO makes recommendations to both the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC).

In preparing its report the GAO reviewed agency documents including reports on Zika virus epidemiology, diagnostic testing guidance, and information on all authorized diagnostic tests for Zika virus disease. The office also interviewed manufacturers of authorized tests, officials from key federal agencies, selected state and local public health entities, and public health organizations responding to the domestic Zika virus outbreak. Diagnostic-related investigation activities included identifying manufacturer and user challenges, characterizing performance of authorized diagnostic tests, and determining the extent to which FDA and CDC followed their own communication guidance.

Testing Concerns

To date the FDA authorized 13 molecular Zika tests and three serologic Zika tests under emergency authorization use. Molecular tests are used to detect genetic material from the Zika virus in serum and urine. Molecular tests are limited for use during the first two weeks after onset of symptoms, when the virus is still present. Serologic tests detect antibodies against the Zika virus, which can be present for roughly four days to 12 weeks post onset of symptoms. However, the presence of similar antibodies from dengue and chikungunya viruses can cross-react and give a positive result.

Molecular and serologic tests have different strengths and limitations, but some of the limitations can be mitigated by using confirmatory testing, as specified in the CDC algorithm. For instance, a negative molecular test does not rule out Zika virus infection because the amount of virus present in the sample could be too small to be detected. The GAO said 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 recommends that molecular tests should be followed by a serological test. To ensure against cross- reactions occur in the serologic testing, the CDC recommends a plaque-reduction neutralization testing (PRNT) to measure Zika virus-specific antibodies. The PRNT test is known to be a highly specialized, but lengthy test. The GAO found that the delays between getting initial antibody test results and the PRNT confirmatory results may have led some clinicians and patients to make family planning decisions without confirmation of Zika virus infection.

Challenges for Diagnostic Test Development

In developing new Zika diagnostic tests, manufacturers faced several challenges.

• An initial lack of knowledge regarding the biological aspects of the Zika virus and human immune response posed challenges to test development, including which sample types were appropriate and how long the virus could persist in different bodily fluids.
• Test developers had difficulty in accessing well-characterized clinical samples. Manufacturers reported to the GAO that quantities of available samples were insufficient, as well as costly.
• Manufacturers also had difficulty accessing FDA-authorized EUA tests (including the CDC’s) for use as a comparator assay in clinical evaluation studies, as recommended by the FDA. The GAO found that CDC initially did not have the capacity to adequately supply public health laboratories and commercial manufacturers with these tests. Ultimately, CDC distributed its tests to four manufacturers through technology transfers. But, only two of 12 authorized molecular diagnostic test labels listed CDC’s test as their comparator test. The GAO writes, “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.” To rectify this, the GAO recommends that CDC establish a transparent process to provide CDC-developed diagnostic tests, on request, to manufacturers that are in the final stages of diagnostic test authorization.

The GAO also cited the FDA for not consistently communicating sufficient information about authorized diagnostic tests, which would enable users to more easily compare performance across different tests. When the GAO compared product labels for different molecular tests, it found that labels listed the type of test used for comparison, but only six of 12 product labels listed the identity of the test used for comparison.

“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,” the GAO writes. As such, the GAO recommended that FDA both consolidate information from individual diagnostic test labels and make it available to enable comparison across tests and that the FDA requires diagnostic manufacturers to list the identity of comparator tests on their labels.