Serial Screening – FDA’s Kobayashi Maru

March 3, 2022By Richard A. Lewis, Senior Regulatory Device & Biologics Expert & Jeffrey K. Shapiro

We return to the subject of FDA’s role in effectively blocking most rapid antigen COVID tests from the U.S. market.  There has not been a new rapid antigen test authorized during the past six weeks.

As we mentioned in our previous post, NIH’s ITAP program was stood up a few months ago to accelerate the validation of these tests and to help companies comply with FDA’s requirements.  That strategy has failed, too.

The new idea is for NIH’s ITAP program to pivot to serial screening.  NIH has been in communication with FDA to finalize a standardized clinical protocol for this purpose.  Unfortunately, based on what we have heard, the process of finalizing an acceptable protocol has hit an unexpected roadblock.  The issue is a conflict between ethical concerns versus study bias.

To explain: Nearly all COVID-19 in-vitro diagnostic trials are single point analyses.  This study design means that the study participant collects a single sample for both the antigen test and the Standard-of-Care device and the participant’s involvement in the study is completed in a single visit.  The participant will usually receive their Standard-of-Care result within 24 hours.

With a serial screening study, however, multiple samples are collected by the participant over a few days.  This fact means that it is possible for the participant to be aware of their “true” COVID-19 status while the trial is still on-going, thus biasing the results.  How does one solve this issue? In order to have an unbiased study the participants in the longitudinal trial should not have knowledge of their COVID-19 status.  At the same time, there are ethical concerns about withholding the Standard-of-Care result from the patient.  If it is withheld, the patient may delay treatment or infect others.

It is interesting that this issue has not surfaced publicly until now.  FDA has allowed serial screening since the issuance of the “Supplemental Template for Developers of Molecular and Antigen Diagnostic COVID-19 Tests for Screening with Serial Testing” on March 16th, 2021 (HPM Blog).  In fact, FDA has authorized a few devices with serial screening claims based on promises by the companies to conduct the studies post-authorization.  To our knowledge, none of those studies have been completed.  This ethical issue may be a reason.  Regardless, this issue seems to be holding up serial testing option.

What should FDA do?  To start, FDA could proceed down the trail that they have already blazed and continue to authorize devices for serial screening using only a single point analysis in order to rapidly expand the supply of tests to the US market.  A few of these tests are already on the market.  To compensate for the lower expected performance, FDA could limit the indications for use of all lateral flow antigen tests to be used in a serial fashion only provided that they meet a lower performance bar that is more consistent with the current state of the pandemic.

Alternatively, FDA could rethink its minimum requirement of 80% sensitivity for rapid antigen tests.  They need to come up with a testing and/or labeling approach that provides reasonable assurance of safety and effectiveness and also harmonizes with the nature of this technology.  The Europeans seem to have done it.  Surely, we can, too.  We floated a few potential solutions here and here.  Under the status quo, the American public will continue to make do without these tests.