On March 17, 2021, FDA granted BioFire Diagnostics’ De Novo, making it the first COVID assay originally authorized on a temporary basis for this public health emergency to be given permanent access to the US market. While FDA has only released the signed letter affirming their permanent marketing status, we can infer a few key points:
1. This De Novo was product of collaboration between FDA and industry over the course of months.
In the letter granting the De Novo it is important to note the date that the De Novo was “Received” by FDA May 19, 2020. This is significant as it means that it is very likely that the candidate device changed from the initial submission to the De Novo being granted. The BioFire® COVID-19 Test was initially authorized by FDA on March 23, 2020 which is well in advance of the DEN200031 being received by FDA.
The BioFire Respiratory Panel 2.1 was submitted for FDA review under EUA202392 meaning that this EUA was originally submitted for FDA review sometime between mid-July and mid-September. As this device was going to ‘set the bar’ for future clearances FDA likely allowed BioFire to add data and indications to the device from the original submission in March through at least October 2, 2020 when the BioFire Respiratory Panel 2.1 was originally authorized as an EUA assay. It is reasonable to assume that if BioFire did not have enough data till mid/late summer to submit an EUA for the BioFire Respiratory Panel 2.1, they did not have enough data for a complete submission back in May 2020.
While this is not typically allowed under normal circumstances it can be viewed as an action to everyone’s benefit as is explained below.
2. A more comprehensive De Novo submission allows for more EUA devices to declare this test as a predicate. The new regulation (21 CFR 866.3981) is as follows:
Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.
As shown by the bolded language, this regulation means that not only can the multitudes of single analyte RT-PCR tests claim this device as a predicate, but also the multiplexed assays will be able to use this De Novo as a predicate and proceed down a less burdensome 510(k) pathway. Furthermore, the regulation is worded to encompass the expected mutation of the virus by defining the measurand as simply “nucleic acid targets” from “microbial agents that cause the SARS-CoV-2 respiratory infection.”
Throughout the pandemic FDA has been very particular about the specific respiratory specimens a device has validated for use. FDA had previous stratified the clinical matrices between the “upper” and “lower” respiratory tracts requiring, in most cases, a representative sample from each. While the BioFire assay is only indicated for nasopharyngeal swabs, the regulation is crafted broadly to encompass samples from all portions of the respiratory tracts.
It appears that this new regulation is only applicable to assays where the measurand is a nucleic acid. This means that both antigen and antibody tests will likely need their own regulations created via the granting of De Novos for their respective technologies.
3. The controversial ‘FDA Reference Panel’ will likely survive the pandemic and fight on to plague industry for years to come. Item 5 of the Special Controls list states the following:
When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device’s labeling under 21 CFR 809.10(b).
The reference panel was FDA’s attempt in the early stages of the pandemic to gain an understanding of assay performance across IVD manufacturers via a single standardized panel. The panel was met with controversy as some test manufacturers were obtaining inconsistent or otherwise confounding results when using the test samples. It appeared to many that the issue was not the tests but the panel. Apparently, there are tests with perfectly good performance that, for some reason or other, are not optimized for the panel.
This use of this panel began showing up in “Conditions of Authorization” for PCR EUAs making the testing compulsory when directed by FDA if a manufacturer wished to stay on the market. In another surprise move, FDA used the performance on their reference panel to rank assays by sensitivity on a public facing website. This website has not been maintained in recent months and is only current as of December 7, 2020.
A manufacturer’s performance with this panel could yield both regulatory and business advantages. If an assay performed well, it afforded the manufacturer the opportunity to pursue an asymptomatic claim for the assay before completing the required clinical study. The device would be considered a ‘more sensitive’ test that would potentially drive new business as a comparator for other assays. Links to the website containing the data from FDA’s reference panel can be found in many of the issued EUA templates:
From FDA’s “Molecular Diagnostic Template for Commercial Manufacturers” regarding “adding population screening of individuals without symptoms or other reasons to suspect COVID-19 to an authorized test”:
If your assay is highly sensitive as determined by testing with the FDA SARS-CoV-2 Reference Panel or a recognized international standard, a post-authorization study may be appropriate.
From FDA’s “Antigen Template for Test Developers” regarding “POC Clinical Evaluation”:
The comparator method should be one of the more sensitive RT-PCR assays authorized by FDA. We encourage you to review the results from the FDA SARS-CoV-2 Reference Panel available here.
Many manufacturers will likely hope that when FDA states “when applicable” in the special controls with respect to the reference panel that FDA means sometime after the eventual heat death of the universe.
4. This submission set the bar for all the other manufacturers wishing to stay on the market post-pandemic.
A key parameter of substantial equivalence is the performance in the clinical agreement study. While OHT-7 typically posts the decision summary for public consumption it has yet to do so for this De Novo (we expect it to be posted in the coming days). While the performance in the decision summary will be the true bar for substantial equivalence, we can look to the labeling for the EUA authorized device to get a preview of what to expect. On page 24 of the labeling, you can find the overall Sensitivity of this device for SARS-CoV-2 is 98% with a Specificity of 100%. We do not know what this performance means for assays that had acceptable clinical agreement as an EUA authorized test (Sensitivity ≥95% and Specificity ≥98%) but do not meet this new bar for performance. As more COVID assay manufacturers scramble to convert their temporary marketing authorization afforded by the EUA pathway into a permanent clearance, these initial devices will be compared to BioFire’s to determine substantial equivalence. If FDA clears a device with a lower sensitivity and specificity than BioFire’s this new device can then be used a predicate for others thereby lowering the bar for substantial equivalence for the rest of industry.
This incremental lowering of acceptable performance standards is a permanent fixture in FDA’s thinking when it comes to clearing device via the 510(k) pathway. Typically, OHT-7 is more intractable than Captain Picard when facing the Borg when comes to clearing a test with lower clinical performance than the declared predicate. We do not yet know how FDA will apply the substantial equivalence paradigm in the future but granting a De Novo to a device with very high clinical agreement could be used as a gating mechanism to weed out devices that were adequate for the pandemic, but not suitable as a permanent fixture in the US market.