Developers of near-patient molecular diagnostic tests encounter the term “CLIA-waived” early in their regulatory planning and often treat it as a single destination. This is not the case. CLIA waiver describes a complexity categorization which includes defining the intended use population and the user environment (Home Use versus Point of Care). These determinations will then guide what kind of study you need to run, and what FDA will expect to see before granting that categorization. Getting those assumptions right at the intended use stage is foundational. Revisiting them after your clinical program is underway is expensive and time consuming.
How tests become waived
Under the Clinical Laboratory Improvement Amendments, all clinical laboratory tests are assigned a complexity category: waived, moderate complexity, or high complexity. The categorization determines what certificate a laboratory must hold to perform the test and what personnel qualifications apply.
Under 42 CFR 493.15, CLIA-waived tests are simple laboratory examinations and procedures that have an insignificant risk of an erroneous result, including those that (A) employ methodologies that are so simple and accurate as to render the likelihood of erroneous results by the user negligible, or (B) the Secretary has determined pose no unreasonable risk of harm to the patient if performed incorrectly. Generally, most CLIA-waived products are required to be simple (per item A), demonstrated through a CLIA waiver application that includes, among other components, an intended-user comparison study in which untrained operators following the labeling achieve results comparable to those of trained laboratory professionals.
There are three pathways through which FDA grants waived status. The first is automatic: tests cleared or approved for use in one of the nine test categories listed in 42 CFR 493.15(c), such as certain urine dipstick tests or non-automated fecal occult blood tests, receive a waived categorization upon marketing authorization. The second is also automatic: tests cleared or approved specifically for home use are categorized as waived upon clearance. The third, and the one most relevant to molecular diagnostic developers, is waiver by application, in which a manufacturer requests waived status as part of a 510(k) or De Novo submission combined with a concurrent CLIA waiver by application (known as a dual submission), or through a separate waiver application filed after initial clearance (a step-wise approach).
For developers of point-of-care (POC) molecular tests, the waiver-by-application pathway is almost always the route. Molecular amplification-based tests have not historically been among the categories that receive automatic waiver. Therefore, demonstrating eligibility through a waiver by application is required.
The POC/OTC distinction: operator and setting, not chemistry
A CLIA-waived point-of-care test is intended for use in a clinical setting that is not a traditional laboratory. Urgent care clinics, physician offices, pharmacies, emergency departments, and school health clinics are common intended use environments for point-of-care molecular tests. Operators in these settings are often healthcare workers rather than laboratory professionals; typically people with limited formal laboratory testing experience. They have not been trained on the specific device and will self-train from device labeling.
A CLIA-waived over-the-counter test is intended for home use by members of the general public: no clinical training, no professional oversight, no access to a colleague when something is unclear. The operator is whoever purchases the test.
That distinction has nothing to do with the assay chemistry and everything to do with where results are generated and by whom. The regulatory requirements that flow from it, for study design, operator recruitment, labeling validation, and human factors, are fundamentally different between the two pathways.
The dual submission and step-wise pathways: a strategic choice
In February 2020, FDA finalized the current CLIA waiver guidance specifically for dual 510(k) and CLIA waiver by application submissions, which allow a manufacturer to seek marketing clearance and waived categorization simultaneously. Dual submission is generally the more efficient path: a single set of comparison and reproducibility studies can support both the 510(k) and the waiver application, and FDA reviews them concurrently. FDA recommends informing the agency of a planned dual submission during the pre-submission meeting and using that meeting to agree on study designs before any clinical work begins.
The step-wise pathway, where a manufacturer first obtains market authorization (510(k) or De Novo) clearance and then files a separate waiver application, remains available. For some programs, it is the more practical sequence: if the initial market authorization study used trained laboratory operators and the data to support waiver were not collected concurrently, a step-wise approach is the only option. The tradeoff is time and cost. A separate waiver application requires a complete intended-user comparison study that may not have been designed to leverage the initial study’s data, and the waived categorization, and the commercial access to waived settings that comes with it, is delayed until the waiver application is reviewed and approved.
For developers entering a new submission, the dual pathway is worth a serious look. The pre-sub investment required to confirm study design is the same either way, and designing one study that supports both objectives is generally more efficient than designing two.
The EUA transition: waiver does not carry over
A significant number of molecular diagnostic developers have products that entered the market under Emergency Use Authorizations during the COVID-19 public health emergency. As those developers now pursue traditional marketing authorization through 510(k) clearance or De Novo, CLIA categorization is a separate and independent question that must be addressed.
Authorization under an EUA does not establish a CLIA complexity categorization that carries over to a traditionally cleared device. An EUA may specify intended care settings, including use at CLIA-waived sites, and some EUA-authorized tests have been designated as waived under the terms of that EUA, but that authorization is specific to the EUA and does not automatically carry forward into a subsequent clearance. When seeking clearance, a developer whose EUA product was used in waived settings must still demonstrate waiver eligibility through the standard waiver application process.
Similarly, waived status for a predicate device does not transfer to a new submission. If the predicate held CLIA waiver, that waiver belongs to the predicate. A new market authorization submission requires an independent demonstration of waiver eligibility, either through a dual submission or through a step-wise waiver application following clearance.
Choosing not to pursue CLIA waiver is sometimes the right call
Not every molecular test should pursue CLIA waiver. Some developers correctly identify that their intended use population is a moderate-complexity clinical environment, such as a hospital-based POC program, a reference laboratory, or a clinical setting where the operators are qualified to perform moderate-complexity testing. In those cases, the commercial objective does not require waived status, and the additional study work to demonstrate it is not justified.
The decision to pursue waiver should follow directly from a clear-eyed look at your intended use claim and your commercial distribution strategy. If your test is intended for professional waived settings, a waiver by application is unavoidable. If it is intended for home use, waived categorization is automatic following clearance, though the evidentiary burden for over-the-counter (OTC) is substantial, as discussed below. If it is intended for moderate-complexity settings and your evidence plan supports that intended use, the waiver program may add cost and timeline without adding proportional commercial value. That is a strategy question that belongs in regulatory planning, not in study design.
The intended use statement is where all of this starts
The intended use statement you write is not an administrative formality. It determines your CLIA pathway, the operators who must be enrolled in your intended-user comparison study, the labeling requirements that apply, and, for OTC, the scope of human factors work required. POC and OTC are not interchangeable designations, and if your commercial strategy eventually includes both professional and consumer channels, the evidence program required to support OTC is not an extension of a POC submission. It is a separate body of work.
Regulatory strategy conversations about intended use and CLIA pathway belong at the front of the development process, before clinical study design begins. They are substantially cheaper there than they are mid-enrollment.
This is the first post in a two-part series on CLIA waiver strategy for molecular IVD developers. Part 2 covers where CLIA waiver comparison studies run into trouble: operator recruitment, site selection, pre-analytical variables, invalid rates, and the study design decisions required for a dual 510(k) and CLIA waiver submission. Read Part 2 here.
Talk to DCN Dx’s Regulatory Affairs team
If you are working through your intended use strategy, evaluating whether to pursue CLIA waiver, planning a dual versus step-wise submission, or navigating the transition from an EUA to traditional marketing authorization, this is the work DCN Dx’s Regulatory Affairs team does. We work with molecular IVD developers across FDA submission pathways, from intended use determination and pre-submission preparation through 510(k) clearance, De Novo authorization, and CLIA waiver. The earlier in your program we engage, the more options you have.
Contact our Regulatory Affairs team or visit dcndx.com/regulatory-affairs-services to learn more about the services we offer.
References
1. U.S. Food and Drug Administration. Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices. February 2020.
