FDA Today | FDA’s diagnostic challenges: Data reporting and antigen tests

For months, the FDA’s top diagnostics regulators have been holding weekly Town Hall meetings where they’ve provided their advice on how to accelerate the development of new tests for COVID-19 and the SARS-CoV-2 virus. Today, we want to take you inside one of those meetings and explain the issues that are vexing FDA and industry this late in the pandemic. AgencyIQ’s Laura DiAngelo has the details for you below.

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Digital reporting processes, antigen tests a focus for FDA’s diagnostics division

The top line: Diagnostic developers are facing new challenges as COVID-19 testing shifts to non-laboratory settings, such as point-of-care and home use tests. One of the biggest challenges: How should the tests’ results be reported? At a meeting held yesterday, CDRH Office of In Vitro Diagnostics and Radiological Health Director Tim Stenzel and Associate Director Toby Lowe addressed some of the issues they’re dealing with and their recommendations on how industry can respond.

First, let’s talk about an unlikely “problem” for regulators: At-home testing and data gaps.

• How results from COVID-19 diagnostic tests are reported depend on where they’re being run. As the pandemic goes on, the sites at which testing takes place is starting to change.
• Since March, the significant majority of diagnostic tests for COVID-19 have been authorized for use in a clinical laboratory (often called a CLIA lab , which refers to their regulatory status). These laboratories, which can be certified at different levels of complexity (e.g., High complexity, moderate complexity), have structures and processes in place by which diagnostic results can be reported out to relevant stakeholders. For example, results may be reported to health care providers, clinical registries and, when necessary, public health authorities such as the state or the Centers for Disease Control and Prevention (CDC).
• However, tests used at the point-of-care (POC) or at home don’t involve a clinical laboratory. POC tests are run by a clinician during a patient visit (e.g., in a doctor’s office, or “CLIA waived” setting), while at-home tests are run independently by a patient and can be either prescription or over-the-counter (OTC).
• Reduced reliance on complex CLIA labs presents both benefits and challenges : First, the laboratory industry has faced significant capacity challenges throughout the pandemic, which led to long turnaround times and decreased access to testing overall. However, moving out of established settings with public health reporting capacity, experience and processes can create so-called “data breaks,” or unreported data. Providers do have the duty to report COVID-19 cases to the relevant authorities, but some data may be lost to follow up. In addition, a test that is run in a patient’s home creates an additional opportunity to lose track of reporting for public health purposes since patients may not report their own data.
• Gaps in data can create concern for the FDA. A diagnostic’s accuracy is only as good as its positive predictive value (PPV) , or the number of total positive results from the test that are actually COVID-19 cases, or “true positives.” However, PPV varies by disease prevalence. In general, areas with lower viral prevalence (i.e., cases) will also have a lower PPV. This means that a clinician’s understanding how to interpret test results relies partially on an understanding of community prevalence of the pandemic. Without adequate reporting, it’s difficult to understand the context of the results.

To address these data gaps, diagnostic manufacturers are being urged by FDA to develop reporting strategies.

• Digital reporting capabilities aren’t technically required by the FDA for it to authorize a diagnostic for use. However, diagnostics chief Tim Stenzel has long maintained that is in the public health interest for test results to be reported to appropriate authorities. Over the past few months as developers work to develop non-laboratory test designs, including those intended for use at POC or at home, Stenzel has urged companies to come up with a plan to ensure that the results are reported.
• Reporting mechanisms include mobile platforms, like smartphone apps. Developers have already seen these in the authorizations of certain POC tests. For example, the Lucira at-home molecular test kit’s November 17 EUA authorization (as a prescription product) included a condition of authorization that the manufacture develop a “mobile smartphone application or website.” This has become a common feature – appearing in other non-lab test authorizations such as the Ellume test kit , for which the federal government recently placed a significant purchase order.
• As a reminder, the intended use of the app is important. Determining what testing is needed for a companion app, and what validation data should be submitted with an EUA, will depend on the app’s intended function. If a manufacturer develops a web-based platform or mobile app that is solely intended to function as a reporting mechanism, in which provider or patient simply logs on after the results have been received to report, this may not need validation data.
• However, if the app is intended to help with the test’s function – for example, guide the user through using the test, take a picture of the test, interpret the results and report out – then FDA will want to make sure that the assessments are “accurate and reliable” when considering authorization, said Stenzel. Any developer considering an app-based system would need to demonstrate to FDA that their app can consistently interpret the test’s results, Stenzel noted.

During the call, Stenzel also addressed a hot topic that’s gotten a lot of media attention: Serial antigen testing.

• Over the counter versus prescription testing. Recently, media publications and some public health stakeholders have called on the FDA to lower its standards for authorizing OTC (i.e., nonprescription) tests. In general, these entities argue that non-prescription tests will significantly increase access to testing in the US.
• FDA agrees, but wants developers to prove it. In response to a question about the FDA’s stance on validation standards for non-prescription tests, Stenzel explained that from his perspective, “Rx [prescription] is a mitigation on risk.” In short, having a clinician available to help a patient interpret their results and decide on next steps provides an extra layer of safety in the diagnostic’s use. Without that assurance, Stenzel explained that “we do ask for additional validation work for [OTC tests]. As long as developers are willing to do those extra steps, we’re willing to give an OTC claim for that assay.”
• The difference between antigen and molecular diagnostics is also a sticking point. Some media reports have highlighted a lack of widespread antigen testing in the US, raising questions about the FDA’s standards for authorization. However, as Stenzel explained, the holdup is largely due to quality and evidentiary concerns. “It’s not a well-kept secret … that it’s a lot harder to develop a good antigen test than a molecular [one],” he said. In addition, while fully scaled manufacture of antigen tests can produce tests at an order of magnitude much greater than molecular tests, standing up antigen manufacturing is particularly difficult. “When they’re good, and when they’re manufactured reliably, which is a hard thing to do,” these tests can and will make a significant impact on public health, said Stenzel. However, the data do need to bear out for agency authorization.
• FDA will decline EUAs where the data doesn’t reflect a high-quality test. “We’re declining two-thirds of serology tests that are coming in,” he noted. While he didn’t have exact numbers for antigen test submissions, “I think that’s probably the same in antigen… it wouldn’t surprise me if the ratio was similar.”

AgencyIQ subscribers can read our full analysis of yesterday’s diagnostics meeting here, including extra details. They can also read our analysis of prior meetings focused on emerging coronavirus variants (even more on that here), antigen tests, regulatory delays , and digital reporting applications.

What we're watching and reading

• … this opinion piece in USA TODAY by investigative journalist Gerald Posner, which seems to sum up one of the current lines of argument against Janet Woodcock becoming nominated as FDA Commissioner. The argument is that Woodcock, as head of the Center for Drug Evaluation and Research, didn’t do enough to prevent or react to the opioid epidemic with the power she had at her disposal. This remains a huge issue for many voters and could act as a lightning rod for criticism by legislators.
• … FDA’s partial rejection of this petition from Public Citizen, which had requested that FDA withdraw the approval of Genzyme’s Seprafilm, a medical device used to treat patients undergoing abdominal or pelvic laparotomy procedures. The device acts to prevent postoperative adhesions between the abdominal wall and organs. Public Citizen alleged the device had not been shown to work in subsequent clinical studies, and that it was associated with “serious, sometimes fatal adverse events.” FDA, however, said it disagreed with Public Citizen’s assessment and that while additional safety warnings were warranted (and have since been released), the device remains effective in the eyes of the regulator.
• … FDA’s approved of its fourth novel drug of 2021, EMD Serono’s Tepmetko – an oncology drug indicated for the treatment of adult patients with Non-Small Cell Lung Cancer with specific mutations (METex14). The drug was given priority review and approved under accelerated approval conditions. EMD Serono said this specific type of NSCLC affects about 3-4 percent of patients and is especially aggressive. In a Phase II, single-arm, open-label, non-randomized study, patients responded to Tepmetko for a median of 11 months.

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