This blog provides an overview of COVID-19 testing authorizations and developments of the COVID-19 pandemic in the United States and Canada. In the world of regulated health care products these tests are known as in vitro diagnostics (IVDs) and fall under the medical device definition in most jurisdictions.
Almost 6 months since both the FDA and Health Canada (HC) issued initial policies and guidances on the COVID-19 test kits (another term used to describe IVDs), there has been a lot of activity from manufacturers and laboratories to get COVID-19 test kits out in the market.
One of the more important aspects of managing the COVID-19 pandemic is keeping up with the demands of testing. In addition to diagnosing the public for suspected cases of COVID-19, testing is also important for monitoring the management of diagnosed patients and assessing those that have been previously exposed but are not currently infected.
IVDs being authorized:
The gold standard test to diagnose a SARS-CoV-2 (virus that causes COVID-19) infection is through nucleic acid-based testing where the test detects viral RNA. This is most commonly achieved through RT-PCR (real time polymerase chain reaction). Viral antigen detection tests are also used for diagnosis. These work by detecting a specific part of the virus on a sample of infected tissue taken from a patient. This test is more rapid than nucleic acid tests however there is a greater chance of not detecting an infection (i.e. false negative), where the patient is often re-tested using a nucleic acid test.
Antibody detection based tests are known as serological testing. These assays are not used to diagnosis infection due to the time lag in patient antibody production. Instead, they are useful for determining exposure to the virus and may help public health authorities gage the extent of COVID-19 transmission. There are limitations: The immunological response is not well defined and the jury is still out on the extent of protective immunity based on past exposure.
Lastly, in the US, tests have been approved to aid in management of patients with COVID-19 and rely on detection of biomarkers related to a more severe inflammatory response.
In the US, IVDs can be class I, II or III and utilize a similar regulatory route as conventional medical devices, e.g. 510(k). Typically, IVDs that diagnose infectious diseases, which have a greater impact on the general public, have a higher classification and require greater evidence of efficacy. However, during a public health emergency the FDA can facilitate expedited authorizations to meet the public need. On February 4th, 2020 the Secretary of the Department of Health and Human Services (which oversees the FDA) determined that manufacturers of IVDs for the detection and/or diagnosis of COVID-19 could place their product on the market using the Emergency Use Authorization (EUA). IVDs authorized for use under the EUA are not considered approved or cleared and have not gone through the scrutiny of a full FDA review. To further assist laboratories and manufacturers, the FDA has issued guidances and EUA templates, which can be found here.
That same day the FDA authorized the Center for Disease Control and Prevention (CDC) to use their 2019-nCoV Real-Time RT-PCR Diagnostic Panel for testing. This was followed by the next two EUAs issued on Feb. 29, 2020 and March 13, 2020. The FDA also issued EUAs to laboratories that have developed their own molecular based tests (collectively termed laboratory developed tests, LDTs) where these tests will only be used by the lab where they were developed. The first EUA for an LDT was issued on March 31, 2020 to Yale New Haven Hospital for their SARS-COV-2 PCR test.
Under Canada’s medical device regulatory framework, IVDs follow the Canadian Medical Device Regulations and regulatory classification follows a risk based approach. As of March 18, 2020 Canada’s Minister of Health issued an Interim Order (similar to the FDA’s EUA) to accelerate regulatory review and approval of COVID-19 related health products including test kits. Also, similar to the US, these IVDs are not considered approved and have not gone through full regulatory scrutiny by Health Canada. The first test kit authorized for use in Canada under the Interim Order was Thermo Fisher’s TaqPathTM COVID-19 Combo Kit. Guidances on Health Canada Interim Order applications can be found here.
By the Numbers (covering February 2020 to end of July 2020):
In the US:
- 162 IVDs and 36 LDTs (molecular laboratory developed tests) authorized under the EUA
- The number of authorizations peaked in June for IVDs and in April for LDTs
- Of the IVDs authorized, 2 are viral antigen detection kits, 35 are antibody based (i.e. serological) and 125 are molecular based (i.e. nucleic acid technology)
- 1 IVD authorized for management of COVID-19 patients. This test looks at severity of the immune response by monitoring interleukin-6 levels in the blood.
- For IVDs, 116 are authorized for use in CLIA labs for high complexity tests, 34 authorized for use in CLIA labs for high/medium complexity tests and 6 authorized for use in CLIA waived labs
- 27 IVDs authorized under the Interim Order since February 2020
- The number of authorizations peaked in March
- 22 are nucleic acid based (i.e. molecular based) and 5 are serological
- 25 are laboratory based, 1 is point of care and 1 is duo laboratory and point of care
- 66 IVDs are currently under review with Health Canada. 54 are lab use and 12 are point of care. 31 are nucleic based and 34 are serological.
To continue following the EUAs see this FDA page, which lists COVID-19 related health products that are issued EUAs along with links to supplementary information on each one. The link for Health Canada’s authorized list is here and the list for devices under review can be found here.
In Canada, a home grown company was touted as a game changer in that their rapid diagnostic was portable and could deliver results in under 60 minutes with goals to reduce that to 30 min. Unfortunately, there were issues with false negative results and Health Canada reversed their Interim Order approval. The device is currently a research-use-only product while the company works to improve test performance.
On June 10, 2020 the FDA issued its first EUA to a diagnostic test that uses next-generation sequence technology. The Illumina COVIDSeq Test by Illumina, Inc. is a qualitative test that can determine the genetic sequence of the viral RNA. This could potentially be used to monitor evolution of the genetic material.
On July 18, 2020 the FDA reissued an EUA to Quest Diagnostics for their Quest SARS-CoV-2 rRT-PCR test to authorize its use with pooled samples. This is an important public health tool where multiple samples from different people can be tested together. If the batch is negative a significant amount of time is saved. If the batch is positive, then retesting is performed on individual samples. This method is especially effective when there is low prevalence of the disease and it is expected that most results would be negative.
Testing for SARS-CoV-2 is critical for diagnosing potential patients and for controlling the spread of the virus. At six and five months since the US and Canada, respectively, issued emergency orders to accelerate market access for COVID-19 test devices, the activity has been great. It is amazing how many companies have been involved with producing test kits. In these extremely hard times it is good to know that government health agencies, private and publicly run labs, and medical device manufacturers can be flexible and assiduous in expediting access to IVDs.
Deborah Pinchev is StarFish Medical’s Toronto QA/RA Manager. She is inspired to write blogs by her interest in helping companies develop and bring to market new and innovative devices.
 For more information on Clinical Laboratory Improvement Amendments (CLIA) see https://www.fda.gov/medical-devices/ivd-regulatory-assistance/clinical-laboratory-improvement-amendments-clia
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