Guidelines for Nucleic Acid-Based In-Vitro Diagnostic Devices

The coronavirus pandemic of 2020 added extreme urgency to the development of diagnostic tests to identify the presence of the coronavirus that causes COVID-19, or of antibodies to the virus. Both the Food and Drug Administration (FDA) and the World Health Organization (WHO) have developed guidelines for nucleic acid-based in-vitro diagnostic devices, and the FDA has revised the guidelines several times since the beginning of the pandemic.

These guidelines address the requirements for emergency use approval for diagnostic devices. The FDA’s most recent guidelines, a revision issued May 11, 2020 and published in the Federal Register on May 15, are advisory only, not mandatory. Other paths to approval may be available, if device developers comply with applicable regulations and laws.

Why Emergency Approval Is Necessary

The explosive spread of coronavirus infections globally created an urgent need for diagnostic tests to facilitate contact tracing and treatment. In the US, infections grew exponentially in the fall, rendering contact tracing nearly impossible. Diagnostic tests are still critical to separate COVID-19 infections from other disease conditions, as well as to identify appropriate treatments and establish whether isolating the patient is necessary.

World Health Organization Emergency Use Listing Procedures

The Director-General of the World Health Organization declared the eruption of SARS-CoV-2 (commonly referred to as COVID-19) to be a public health emergency of international concern (PHEIC) on January 30, 2020. On February 28, 2020, the WHO invited manufacturers of nucleic acid-based in-vitro diagnostic devices that detect SARS-CoV-2 to apply for emergency use listing (EUL).

In April, the WHO extended its invitation to makers of rapid diagnostic tests that detect antibodies. WHO further extended the invitation to immunochromatographic (lateral flow) or immunofiltration (flow-through) RDT tests that detect SARS-CoV-2 antigens in June 2020.

Under WHO EUL application procedures, vaccines, therapeutics, and in-vitro diagnostics must meet specific requirements to be eligible for EUL evaluation. Mandatory criteria include:

  • The disease the product is intended to address is serious or immediately life-threatening, and has the potential to cause an outbreak, epidemic, or pandemic. There must be a good reason for the WHO to employ emergency use listing procedures, such as the lack of any existing, licensed products for the indicated use, or that are targeted toward a specific population in peril.
  • Existing products, if they exist, have not been effective in preventing outbreaks or eliminating the disease.
  • The manufacture of medicines or vaccines comply with Good Manufacturing Practices (GMP), and in the case of in-vitro diagnostic devices, under a working Quality Management System (QMS).
  • The company applying for EUL agrees to complete the development of the product, including validation and verification for IVDs, once the product is licensed.

FDA Advisory Guidelines for Four Categories of Tests

In the US, the FDA followed a similar timeline to issue guidelines to encourage the development of diagnostic tests for SARS-CoV-2. The Department of Health and Human Services (HHS) declared a public health emergency on January 31, 2020. On February 4, 2020, the Secretary of HHS added a determination that the circumstances justified emergency use of in-vitro diagnostics to identify the presence of the virus or evidence of an infection.

The FDA has announced revisions to its Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency on March 16, May 4, and May 11, 2020. These guidelines were issued to facilitate the development and use of testing for SARS-CoV-2 during the emergency. The guidelines address four types of testing scenarios.

Two of the policies intended to accelerate the development of laboratory tests apply, one for tests that will be submitted for emergency use authorization (EUA), and the other for tests developed under existing state guidelines, where the state takes responsibility for testing by labs in that state.

One policy is designed to allow manufacturers to more quickly deliver their validated tests to laboratories for specimen testing while preparing the EUA application for submission to the FDA. The fourth policy applies to uses of serological testing.

The overall purpose of the guidelines and their revisions was to accelerate rapid testing availability in the US while also ensuring that the new tests would be accurate and reliable. In-vitro diagnostics product development became a priority, as testing is critical to assess and contain the spread of infection.

The guidelines emphasize the critical role of validation. The implications of false results in the midst of a public health emergency extend far beyond the individual patient, affecting the general public nationwide. The guidelines include recommendations about validation and encourage manufacturers to discuss any alternative validation methods with the FDA.

In response to concerns about inappropriate promotion or poor performance, the revised guidelines ask manufacturers to apply for an EAU within 10 days of notifying the FDA of validation that occurs while preparing the application for an EUA. The guidelines allow commercial manufacturers to deliver newly developed serology tests to laboratories while applying for the EUA.

However, the guidelines caution laboratories that until an EUA that authorizes additional testing environments for a specific test is issued, use of the newly developed tests is limited to laboratories certified to perform high-complexity testing. Point-of-care use is limited to environments covered by the laboratory’s CLIA certificate for high-complexity testing.

The FDA won’t object to serology tests developed in laboratories, rather than by commercial manufacturers, that are not for diagnostic purposes which the lab has validated and that are being performed at one laboratory that is CLIA-certified to perform high-complexity testing. The guidelines state that the FDA believes its time is better spent reviewing the EAU applications from commercial manufacturers.

However, the guidelines warn that if the FDA becomes aware of questions or concerns about poor performance or misleading statements about a lab-developed serology test, the agency will communicate those concerns to the laboratory and provide the laboratory an opportunity to address them. If the lab doesn’t respond in a timely manner, it may be removed from the listing of notifications and may be subject to additional actions the FDA deems appropriate.

The guidelines make specific recommendations about validation, notification, and labeling applicable to CLIA-certified laboratories and commercial manufacturers.

Manufacturers are encouraged to post detailed instructions and information to avoid confusion about the purpose of the test and the meaning of the results. These include labeling recommendations such as:

  • Informing the user that the test has not been approved by the FDA;
  • Explaining that negative results of an antibody test don’t necessarily mean that no infection exists;
  • Stating that results of an antibody test shouldn’t be used to diagnose or rule out SARS-CoV-2 infection; and
  • Stating that positive results may indicate a past infection with a different strain of coronavirus.

The full guidelines document is available on the FDA website as a PDF, which also provides a link to the Federal Register summary.

Guidelines for Nucleic Acid-Based In-Vitro Diagnostic Devices