TABLE 1.

Comparison of regulatory requirements for studies of influenza tests used in clinical settings and home settings^a

Component	Tests for clinical sites	Tests for home use
Intended use operator and intended use site	HCW at clinical sites. Nonlaboratorians but may have experience with other tests and typically have training as part of site quality control, samples collected by HCW, potentially reduced operator diversity compared to general population, recruitment targeted to people naturally seeking care.	Diverse, untrained, first-time users at nonclinical sites, including home. Operators may not have any experience with diagnostic test procedures or underlying medical knowledge, training opportunity and effectiveness may be less than that of HCW, likely higher user diversity than that of HCW population, potential recruitment bias if health-seeking behavior is not natural.
	Study design: 3 sites, 3 representative operators per site testing in their typical workflow, diversity of operator skill is narrowed by medical training.	Study design: Intended sites are decentralized (e.g., home), but study design may allow for contrived study sites. Test operators should be inexperienced individuals with diversity representative of the intended population (e.g., age, education).
Intended use population (criteria to test)	HCW determines who to test, typically patients with symptoms during flu season. Patients present at clinic later in disease and may represent more severe disease (spectrum bias).	For Rx home use test, HCW retains control over who to test. For an OTC test, testing is self-determined, potentially addressed by labeling but not enforceable.
	Study design: Recruitment at clinical site matches intended use; eligibility criteria ensured by in-person HCW.	Study design: Recruitment at clinical site does not match intended use but allows greater certainty of eligibility criteria. Community recruitment with monetary incentive may bias study sample, especially inclusion criteria based on self-reporting. Enrollment may be based on motivation of getting a test result.
Sample type and collection	Typically use well-established best-known sampling methods performed by HCW; new methods require validation, allowing future tests to adopt new methods.	Non-HCW collection sampling methods may be limited. Sampling may need to consider self-collection, parent-child collection, adult-adult collection. More restricted options for self-sampling may drive less-proven sampling methods; new methods will require (“bridging”) validation studies.
Reference standard/comparator	Best-known sample (e.g., NP swab) collected by HCW and tested by high-quality laboratory method.	Best-known sample collected by HCW may not be possible in some study designs. Self-collected reference sample may require validation.
Usability/human factor study	None	Essential. FDA recommends human factor study before clinical study. Healthy population in a contrived setting is acceptable. Near-the-cutoff studies (see below) can be performed on the same population.
Analytical studies	LOD (analytical sensitivity), inclusivity (analytical reactivity), cross-reactivity (analytical specificity), microbial interference, endogenous/exogenous interfering substances.	Same as tests for clinical sites.
Flex studies	Established framework and specific guidance available (1, 42). Performed in laboratory by study staff.	Same as CLIA waiver but should address new and elevated risks for diverse, untrained, first-time users and variations in home use environment. These include ambient temp and humidity, lighting conditions, reading time, testing delays, sample and diluent vol, sample elution technique, disturbances, and orientation during analysis, if applicable, to the specific test under study (6).
Stability/shelf life studies	Stored in clinical setting.	Stored at home with no oversight or enforcement.
Reproducibility panel (near the cutoff, performance near LOD)	Contrived samples near the LOD (spiked human matrix); performed by operators similar to clinical samples.	Contrived samples near the LOD (spiked human matrix); usability study group is a candidate for this testing.
Implementation: product labeling	HCW interprets labeling and ensures clinical oversight.	Rx home use: HCW interprets labeling and enforces clinical oversight. OTC: Users must be capable of understanding and following labeling, but this cannot be enforced.
Implementation: product disposal	Sites have disposal systems in place (e.g., sharps, biohazardous materials).	Need to dispose in usual household waste.
Implementation: connection to care and reporting	Inherently connected to care. Sites have reporting systems in place for notifiable diseases.	Rx home use: Connected to care and usual reporting systems. OTC: No connection to care, or care must be initiated by user, no reporting requirements.
Implementation: product postmarket surveillance	Medical oversight and reporting increase chance of observing emerging problems with performance.	Potential medical or public health oversight if reporting of test results is enforced but lack of context to recognize problems.

^aHCW, health care worker; OTC, over the counter test; Rx home use, prescription-based home use test; NP, nasopharyngeal; LOD, limit of detection.