On March 16th, 2021 CDRH announced a major policy change for the EUA program in an effort to expedite screening testing for the pandemic. Screening is the testing of asymptomatic individuals who do not have known or suspected exposure to COVID-19 in order to make individual decisions based on the test results. This new supplemental template provides recommendations for device manufacturers with the goal:
to streamline the authorization of screening tests with serial testing. The recommendations apply to test developers who seek an EUA from the FDA for certain screening tests prior to conducting certain performance evaluations with asymptomatic individuals.
This is a major departure from previous policy as testing prior to authorization was only permissible in very limited cases for devices used only in High Complexity CLIA labs. It is important to note that this new pathway is only available to manufacturers of molecular and antigen tests. Serology tests are not mentioned in this announcement.
Serial testing as defined by FDA is the “testing the same individual multiple times within a few days.” The thinking behind this strategy is the testing of a single patient across multiple days would increase the chances of detecting infection even when using devices with lower sensitivity. FDA’s expectations for a device’s Sensitivity/Specificity increase when you traverse across the continuum of indications. We provide an example for antigen tests below (Table 1).
Table 1 – Performance Expectations by Indication in FDA’s EUA Templates (Antigen)
|CLIA Lab||Point-of-Care||Rx-Only Home-Use (Symptoms Confirmed)||Rx-Only Home-Use (Suspected Exposure)||
(Asymptomatic or No Suspected Exposure)
|PPA = Positive Percent Agreement; NPA = Negative Percent Agreement|
The key section of this announcement is where FDA identifies what indications may be eligible for this new program:
For example, in certain circumstances, a [point-of-care] test or an at-home test could be authorized for over-the-counter (OTC) use without the need for validating its use in asymptomatic individuals prior to authorization.
This statement has the potential to be both very powerful and very frustrating for industry. In Table 2 below there is a breakdown of the data expectations for Point-of-Care, Prescription Home Use, and OTC Home Use with an asymptomatic claim. What you can see from the information, in the various EUA templates laid-out in this fashion, is that ‘Prescription Home Use’ and ‘OTC Home Use’ are very similar in their requirements. It is, therefore, reasonable to expect FDA to blur the line between ‘Prescription Home Use’ and ‘OTC Home Use’ when considering asymptomatic testing. It was very surprising, however, to read that this new policy may also apply to devices validated for Point-of-Care. The differences in data requirements between ‘Point-of-Care’ and ‘OTC Home Use’ are substantial. Devices authorized for Point-of-Care are not validated to the same degree with respect to Robustness (Flex Studies), Human Factors (Human Usability), the data required to substantiate performance for Point-of-Care (POC) may have been largely retrospective testing. This difference is due, in part, to the intended users – tests intended for POC are typically used by healthcare providers whereas home tests are used by lay people.
The inclusion of Point-of-Care in this new policy implies that a manufacturer can take their authorized test, supplement the EUA with the additional information describing serial testing and obtain an OTC Home-Use indication. As of March 16, there are twenty (20) molecular EUAs and one (1) Antigen EUA with an attribute of ‘screening’ according to FDA’s website. Of these tests, eight (8) are Direct-to-Consumer (DTC) and two (2) are Over-the-Counter (OTC). To date, there are no Point-of-Care EUAs with a screening attribute.
Table 2 – Tests Recommended by FDA Stratified by Indication
|Point of Care (POC)||Prescription Home Use||OTC Home Use (asymptomatic)|
|Limit of Detection||X||X||X|
|High Dose Hook Effect||X||X||X|
|Test Kit Stability||X||X||X|
|Control Materials (high-volume sites only)||X|
|SARS-CoV-2 Variant Analysis1||X||X||X|
|Point-of Care Clinical Agreement (Combination Prospective/Retrospective)||X|
Flex Studies for Point-of-Care
Expanded Flex Studies for Home Use
|All Comers Testing (Prospective)||X||X|
|Self-Testing or Testing of Minors (Prospective)||X||X|
|1FDA has announced plans to update the EUA Temple, but has yet to do so for Antigen tests|
|2 FDA expects 30 Participants for Rx Only and 100 Participants for OTC|
Supplemental Template for Developers of Molecular and Antigen Diagnostic COVID-19 Tests for Screening with Serial Testing (Example Template)
The administrative section at the top of this new template echoes the announcement indicating that this policy applies to Point-of-Care indications:
This template is intended to provide supplemental recommendations for developers of molecular and antigen tests seeking claims for screening with serial testing without studying asymptomatic individuals prior to authorization, including for point-of-care (POC) and at-home tests.
While the intention of the policy is to increase testing availability FDA does not want manufacturers to misconstrue this as a paradigm shift with an opportunity to resurrect denied EUAs from the grave.
These recommendations will generally not be applicable to developers with tests for which data has already demonstrated poor performance (e.g., less than 80% PPA) for testing asymptomatic individuals.
FDA later goes on to seemingly contradict themselves on the next page of the template by stating:
As discussed in the Antigen Template for Test Developers, strategies for serial testing with less sensitive tests (i.e., PPA <80%) may be able to be support authorization
FDA gives the following example as a modification to the intended use:
…individuals without symptoms or other epidemiological reasons to suspect COVID-19 infection, when tested twice over two (or three) days with at least 24 hours (and no more than 36 hours) between tests.
As written, this implies that there is no expected modification to the intended use setting or user as a result of this policy change.
The template does indicate that FDA intends to push as much of the clinical validation as possible to a post-marketing commitment in order to expedite the authorization of new tests. While this recommended study size is small, 20 asymptomatic positives individuals, it has been increasingly more difficult to find asymptomatic positives naturally within the population, and that challenge is likely to continue to grow. It is not clear from this template how long FDA will give these companies to compete these post-authorization studies.
The template closes with a final recommendation for labeling:
Proposed labeling should clearly identify the population in which the test’s performance has been validated, and clearly identify any populations included in the intended use for which the test’s performance has not yet been established and will be established during the above referenced post-authorization study.
This final section further confuses what is expected of manufacturers as it implies that the post-authorization study is the only data requirement to expand the EUA claim to a new patient population.
This announcement from FDA generates a rollercoaster of emotion starting with cautious optimism, to elation, and finishing with confusion. This policy raises major administrative questions that need to be answered in full if this new program is to have a chance at success.
Can a manufacturer take an existing Point-of-Care or Rx-Only EUA and convert it to an OTC Authorization, if they commit to conducting an additional clinical study post-authorization?
It is our review of the policy that, as written, it appears that the answer is yes. However, the policy never mentions the non-clinical tests that FDA typically requires for Home-Use tests and whether those will also need to be performed, either pre- or post-market, to support the expanded indication Point-of-Care authorized tests. Without additional clarifications on the part of FDA, manufacturers will be left scratching their heads and unsure as to what FDA expects in EUAs moving forward.
The next “FDA Virtual Townhall” is Wednesday March 24th at 12:15 pm (ET). See you there.