FDA REGULATORY ISSUES[1]
The advent of the COVID-19 rapid antigen test launched at-home diagnostics to the forefront of conversation in the life sciences industry. Many believe this is only the beginning. As the share of telehealth services increases, drawing interest away from traditional healthcare services models, startups and established companies alike are positioning themselves to take advantage of the growing market for technologies and products that enable non-lab-based diagnostics capable of being purchased without a prescription and conducted entirely at home.[2] MoFo’s FDA Regulatory team has described the top three issues developers of these tests should consider.
- Understand Your Regulatory Obligations
Companies considering entering the over-the-counter (OTC) diagnostic test space should fully understand their regulatory obligations. FDA has authority to regulate in vitro diagnostics (IVDs) for end-to-end use at home (such as pregnancy tests or COVID rapid tests) under both the Federal Food, Drug, and Cosmetics Act (FDCA) and the Public Health Service Act.[3] This regulatory authority extends throughout the product lifecycle, from premarket clinical studies to post-market obligations like adverse event reporting and manufacturing controls.
a. OTCs Are Not LDTs
FDA has issued a significant rulemaking proposal to regulate “laboratory developed tests” (LDTs), a category that FDA has not actively regulated in the past, citing a policy of “enforcement discretion.” [4] The proposed changes to FDA’s regulations do not specifically define LDTs, but the proposed rule would add language to the regulatory definition of IVD to clarify that laboratories may be deemed manufacturers of IVDs and thus subject to regulation.
However, FDA’s rulemaking around LDTs would not apply to OTC tests. In the past and in the preamble to the proposed rule, FDA defines LDTs as tests that are “designed, manufactured and used within a single laboratory.”[5] When FDA uses the term “OTC,” it means a test for which the end user collects a specimen at home and performs the test at home. Although there is often thought to be some overlap between tests that use “self-collected” specimens[6] and LDTs, OTC tests, by definition, cannot be LDTs and have never been the subject of FDA’s enforcement discretion.
b. Premarket Review
For IVDs sold OTC, premarket review is required because FDA generally considers these tests, as a category, to be moderate-risk or high-risk.[7] This means that FDA will likely require a de novo review for a test that has no legally marketed predicate. If there are already similar tests on the market, it may be possible to obtain clearance through the generally less-burdensome 510(k) process.[8] Companies undergoing premarket review for an OTC test should plan to complete a user-comprehension test and/or usability study, as well as prepare for FDA to review the product’s accuracy, reliability, clinical validity, and claims.
A de novo request will include a description of the “probable benefits of the device when compared to the probable or anticipated risks when the device is used as intended.”[9] For OTC devices, risks might include “misinterpretation or over-reliance on device output,” which might be addressed through human factors and usability engineering testing under simulated conditions of use, and risk mitigation measures, including appropriate information within labeling.[10]
c. Post-market Obligations
Even after regulatory clearance or approval has been granted, a cleared or approved product and its manufacturer are subject to extensive regulatory requirements relating to manufacturing, labeling, packaging, adverse event reporting, storage, advertising, and promotion for the product.
Companies launching a new diagnostic product, as well as companies converting a lab-based test to an at-home test, should carefully consider labeling. The label must contain adequate information so that a lay user can select the device as an appropriate match for their condition, understand how to use the device, correctly interpret the results, and appropriately manage their condition—all without assistance from a healthcare provider.[11] Such information includes the test’s intended use, recommended procedures from specimen collection to results, test limitations, specific performance characteristics, and list of interfering substances.[12]
Any advertising or promotion of the product should strictly adhere to the FDA-cleared indication, and any claims made about the safety or efficacy of the product should be consistent with any FDA-cleared or approved labeling. This is an area where many companies have struggled and faced not only enforcement actions from FDA but also civil and criminal enforcement for false claims made to government healthcare programs.
Device manufacturers are required to follow FDA’s Quality System Regulation (QSR), a complex regulatory scheme that covers the procedures and documentation of the design, testing, production, process controls, quality assurance, labeling, packaging, handling, storage, distribution, installation, servicing, and shipping of their marketed products. FDA enforces QSR and other requirements through periodic announced and unannounced inspections of manufacturing facilities.
Medical Device Reporting (MDR) is one of the post-market surveillance tools the FDA uses to monitor device performance, detect potential device-related safety issues, and contribute to benefit-risk assessments of these products. Mandatory reporters, including manufacturers, device user facilities, and importers, must submit to FDA certain types of reports for adverse events and product problems about medical devices.
- Talk to FDA Early and Often or Face the Consequences
Companies considering launching an at-home diagnostic test should consult with FDA early and often. Proactive communication generally limits unexpected regulatory hurdles, clarifies the regulatory costs associated with bringing a test to market, and may help prevent regulatory tangles. Using tools like the pre-submission process to ask clarifying questions of the relevant review division prior to making a submission can save valuable time and avoid wasting resources on studies that will not satisfy FDA’s requirements.
When test companies do not comply with their regulatory obligations, FDA has a number of enforcement tools that it can employ. Failure to comply with the regulatory requirements of the FDA may cause a company to be subject to administrative or judicially imposed sanctions, including restrictions on the products, manufacturers, or manufacturing process; adverse inspectional observations (Form 483), warning letters, or untitled letters; civil or criminal penalties or fines; injunctions; product seizures, detentions, or import bans; voluntary or mandatory product recalls and publicity requirements; suspension or withdrawal of regulatory clearances or approvals; total or partial suspension of production; imposition of restrictions on operations, including costly new manufacturing requirements; refusal to clear or approve pending applications or premarket notifications; and import and export restrictions.
- Keep COVID-19 Lessons in Mind
As noted above, the COVID-19 pandemic marked a turning point in consumer demand for at-home diagnostics and more widespread dissemination of information about how FDA thinks about this category diagnostics, but did not necessarily make it easier to bring an OTC diagnostic test to market. Recognizing this shift in the IVD market, FDA has now created a searchable database for approved OTC diagnostic tests, linking would-be test developers to more readily available details about FDA’s review of those tests. FDA also issued guidance documents, templates, and summary review documents to aid the development of rapid antigen tests that shared learnings from the COVID-19 experience, highlighting the issues that were a focus of FDA oversight.[13]
Companies looking to bring at-home diagnostics to market can learn from FDA’s regulation of COVID rapid tests by not underestimating the data requirements. During the pandemic, FDA required OTC COVID rapid test manufacturers to meet high accuracy standards, as well as conduct separate usability studies.[14] After rapid tests were slow to come to market, the agency’s approval process was criticized as too stringent.[15] While FDA has vocally supported increasing at-home diagnostic testing, the same high standards that applied to COVID rapid tests continue to be used for all OTC diagnostic tests. By fully understanding and planning to meet stringent standards, companies can be better prepared for the premarket review process.
[1] This is the third in a series of three articles addressing the licensing and regulatory considerations for at-home diagnostic companies. The first article focuses on issues in structuring customer agreements and can be found [here]. The second focuses on issues in structuring manufacturer, supplier, and vendor agreements and can be found [here].
[2] Some diagnostic tests are marketed “direct-to-consumer,” but the consumer is not able to perform the entire test because the self-collected specimen must be analyzed by a laboratory. This article deals exclusively with tests that can be performed end-to-end by the consumer. We note, however, that FDA has recently issued a rulemaking proposing to regulate laboratory developed tests (LDTs), a category that FDA claims has long been subject to enforcement discretion. That proposal clearly distinguishes between tests performed by the consumer at home from LDTs, noting that OTCs have never been the subject of FDA’s enforcement discretion.
[3] 21 C.F.R. § 809.3(a).
[4] FDA, Proposed Rule: Medical Devices; Laboratory Developed Tests, 88 Fed. Reg. 68006 (Oct. 3, 2023).
[5] FDA, Draft Guidance for Industry, FDA, and Clinical Laboratories: Framework for Regulatory Oversight of LDTs (Oct. 2014), https://www.fda.gov/media/89841/download.
[6] This article deals exclusively with tests that can be performed end-to-end by the consumer. We note that some diagnostic tests that use self-collected specimens are marketed as “direct-to-consumer” (DTC) tests. This category is outside the scope of this article because the consumer is not able to perform the entire test, i.e., the sample must be analyzed by a laboratory.
[7] Direct-to-Consumer Tests, U.S. Food & Drug Admin., https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests (last visited October 9, 2023).
[8] For a diagnostic test to be cleared for its intended use, FDA must find that the product is substantially equivalent to a legally marketed predicate device. See 21 U.S.C. §§ 360c(i) & (f)(1); see also FDA, Guidance for Industry and FDA: The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications (July 2014).
[9] FDA Website, Over-the-Counter (OTC) Medical Devices: Considerations for Device Manufacturers, https://www.fda.gov/medical-devices/products-and-medical-procedures/over-counter-otc-medical-devices-considerations-device-manufacturers.
[10] Id.
[11] Over-the-Counter (OTC) Medical Devices: Considerations for Device Manufacturers, U.S. Food & Drug Admin., https://www.fda.gov/medical-devices/products-and-medical-procedures/over-counter-otc-medical-devices-considerations-device-manufacturers (last visited October 9, 2023).
[12] In Vitro Diagnostic Device Labeling Requirements, U.S. Food & Drug Admin., https://www.fda.gov/medical-devices/device-labeling/in-vitro-diagnostic-device-labeling-requirements (last visited October 9, 2023).
[13] See, e.g., FDA, Molecular and Antigen Home Use Test Template, https://www.fda.gov/media/140615/download; FDA, In Vitro Diagnostics EUAs – Antigen Diagnostic Tests for SARS-CoV-2, https://www.fda.gov/medical-devices/covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-antigen-diagnostic-tests-sars-cov-2.
[14] William Rinehart, Improving the FDA: Lessons Learned from COVID-19 Rapid Tests 9 (Center for Growth and Opportunity at Utah State University 2023).
[15] Id. at 8–11.